Bicyclo 2,2,2!octane derivatives

ABSTRACT

The compounds of the formula I ##STR1## and their pharmaceutical acceptable salts, which are defined herein, are ligands for cholecystokinin and/or gastrin receptors.

This application is a continuation-in-part of PCT/GB93/00346 filed Feb.19, 1993. The benefit is hereby claimed of the right to an earliereffective filing date based on PCT/GB93/00346 as provided for in 35 USC§120.

This application is a continuation-in-part of PCT/GB93/00346 filed Feb.19, 1993. The benefit is hereby claimed of the right to an earliereffective filing date based on PCT/GB93/00346 as provided for in 35 USC§120.

This invention relates to bicyclo 2.2.2!octane derivatives, and moreparticularly to bicyclo 2.2.2!octane derivatives which bind tocholecystokinin and/or gastrin receptors. The invention also relates tomethods for preparing such bicyclo 2.2.2!octane derivatives and tocompounds which are useful as intermediates in such methods.

Gastrin and CCK's are structurally-related neuropeptides which exist ingastrointestinal tissue and in the CNS (see Mutt V., GastrointestinalHormones, Glass G. B. J., ed., Raven Press, N.Y., p 169 and Nisson G.,ibid, p. 127).

Gastrin is one of the three primary stimulants of gastric acidsecretion. Several forms of gastrin are found including 34-,17-, and14-amino acid species with the minimum active fragments being theC-terminal tetrapeptide (TrpMetAspPhe-NH₂) which is reported in theliterature to have full pharmacological activity (see Tracey H.J. andGregory R.A., Nature (London), 1964, 204, 935). Much effort has beendevoted to the synthesis of analogues of this tetrapeptide (and theN-protected derivative Boc-TrpMetAspPhe-NH₂) in an attempt to elucidatethe relationship between structure and activity.

Natural cholecystokinin is a 33 amino acid peptide (CCK-33), theC-terminal 5 amino acids of which are identical to those of gastrin.Also found naturally is the C-terminal octapeptide (CCK-8) of CCK-33.

The cholecystokinins are reported to be important in the regulation ofappetite. They stimulate intestinal motility, gall bladder contraction,pancreatic enzyme secretion, and are known to have a trophic action onthe pancreas. They also inhibit gastric emptying and have variouseffects in the CNS.

Compounds which bind to cholecystokinin and/or gastrin receptors areimportant because of their potential pharmaceutical use as antagonist ofthe natural peptides.

A number of gastrin antagonists have been proposed for varioustherapeutic applications, including the prevention of gastrin-relateddisorders, gastrointestinal ulcers, Zollinger-Ellison syndrome, antral GCell hyperplasia and other conditions in which lowered gastrin activityis desirable. The hormone has also been shown to have a trophic actionon cells and so an antagonist may be expected to be useful in thetreatment of cancers, particularly in the stomach and the colon.

Possible therapeutic uses for cholecystokinin antagonists include thecontrol of appetite disorders such as anorexia nervosa, and thetreatment of pancreatic inflammation, biliary tract disease and variouspsychiatric disorders. Other possible uses are in the potentiation ofopiate (e.g. morphine) analgesia, and in the treatments of cancers,especially of the pancreas. Moreover, ligands for cholecystokininreceptors in the brain (so-called CCK_(B) receptors) have been claimedto posses anxiolytic activity.

According to the present invention, there is provided a method forcounteracting an effect of cholecystokinin or gastrin in a patient, saidmethod comprising administering to said patient an effective amount of acompound of the formula ##STR2## wherein W is a carbonyl, sulphonyl orsulphinyl group, and X is a carbonyl, sulphonyl or sulphinyl group or-C(O)-CH₂ - (in which the carbonyl group is bonded to Y), provided thatat least one of W and X contains carbonyl,

Y is R₇ --O-- or R₇ --N(R₈)-- (wherein R₇ is H or C₁ to C₁₅ hydrocarbyl,up to two carbon atoms of the hydrocarbyl moiety optionally beingreplaced by a nitrogen, oxygen or sulphur atom provided that Y does notcontain a --O--O-- group, and R₈ is H, C₁ to C₃ alkyl, carboxymethyl oresterified carboxymethyl),

Z is selected from

i) --O--R₉

wherein R₉ is H, C₁ to C₅ alkyl, phenyl, substituted phenyl, benzyl orsubstituted benzyl;

ii) ##STR3## wherein Q is H, C₁ to C₅ hydrocarbyl, or --R₁₀ --U, whereinR₁₀ is bond or C₁ to C₃ alkylene and U is aryl, substituted aryl,heterocyclic, substituted heterocyclic or cycloalkyl;

iii) ##STR4## wherein a is 0 or 1 and b is from 0 to 3, R₁₁ is H ormethyl,

R₁₂ is H or C₁ to C₃ alkyl; or R₁₂ is CH₂ ═ and Q' is absent; or R₁₁ andR₁₂ are linked to from a 3- to 7-membered ring,

R₁₃ is a bond or C₁ to C₅ hydrocarbylene,

G is a bond, --CHOH-- or --C(O)--

Q' is recited above for Q or --R₁₀ --(C(O))_(d) --L--(C(O)_(e) --R₉(wherein R₉ and R₁₀ are as defined above, L is O, S or --N(R₁₄)--, inwhich R₁₄ is as defined above for R₈, and d and e are 0 or 1, providedthat d+e<2); or Q' and R₁₂, together with the carbon atom to which theyare attached, from a 3 to 7-membered ring,

Q is defined above, or Q and R₁₂ together form a group of the formula--(CH₂)_(f) --V--(CH₂)_(g) -- wherein V is --S--, --S(O)--, --S(O)₂ --,--CH₂ --, --CHOH-- or --C(O)--, f is from 0 to 2 and g is from 0 to 3;or when Q' is --R₁₀ --U and U is an aromatic group, Q may additionallyrepresent a methylene link to U, which link is ortho to the R₁₀ link toU,

T is H, cyano, C₁ to C₄ alkyl, --CH₂ OH, carboxy, esterified carboxy oramidated carboxy; or

iv) ##STR5## wherein A and B are independently a bond or C₁ to C₃alkylene, provided that A and B together provide from 2 to 4 carbonatoms in the ring, R₉ and R₁₀ are as defined above, and R₁₅ is asdefined above for R₈

or Z is absent and W is H,

R₁ is H, methyl, halo, carboxy, esterified carboxy, amidated carboxy,carboxymethyl, esterified carboxymethyl or amidated carboxymethyl,

R₂ is selected from the groups recited above for R₁ ; or,

when Z is absent and W is H, R₂ may additionally represent --C(O)--Z'wherein Z' is selected from the groups recited above for Z; or R₁ and R₂together form a second bond between the carbon atoms to which they areattached,

R₃ R₄ (or each R₃ and R₄ group, when m or n is 2 or more) areindependently selected from halo, amino, nitro, cyano, sulphamoy,sulphonyl, trifluoromethyl, C₁ to C₃ alkyl, C₁ to C₃ alkoxy, hydroxy, C₁to C₃ hydroxyalkyl, C₁ to C₃ alkylcarboxyamino, carboxy, esterifiedcarboxy and amidated carboxy

R₅ and R₆ are independently selected from H and the groups recited abovefor R₃

m is from 0 to 4, provided that m is not more than 2 unless R₃ isexclusively halo,

n is from 0 to 4, provided that n is not more than 2 unless R₄ isexclusively halo,

or a pharmaceutically acceptable salt thereof.

A number of compounds falling within the above definition are known fromU.S. Pat. No. 3,950,407; Weber et al, J. Org. Chem. 53, 5831-9 (1988);Czugler et al, J. Chem. Soc., Chem Commun. (23), 1632-4 (1984); Russellet al, J. Am. Chem. Soc. 94(5), 1693-8 (1972); Chem. Abs. 73, no. 3689z(1970); and Singh et al, Ind. J. Chem. 23B, 631-4 (1984). However,compounds according to the above definition are believed to be novel perse, provided that

if one (but only one) of R₁ and R₂ is methyl, m and n are not both 0,

Z is not hydroxy or methoxy when Y is hydroxy or methoxy,

Z and Y are not trans to each other when Z is R₈ --O-- and Y is R₇--O--,

--X--Y does not equal --W--Z when R₁ ═R₂ ═H and m═n═0, and if Z isabsent and R₁ and R₂ are both H, Y is not R₇ --O--

and further provided that the compounds are not7-(N,N-dimethylaminocarbonyl)-8-methyl-2,3,5,6-dibenzobicyclo2.2.2!octane or7-(N-methyl-N-phenylaminocarbonyl)-8-methyl-2,3,5,6-dibenzobicyclo2.2.2!octane.

CCK inhibitors of different structures are disclosed in EP-A-0405537 andU.S. Pat. No. 3,577,366.

The invention also comprehends derivative compounds ("pro-drugs") whichare degraded in vivo to yield the species of formula (I). Pro-drugs areusually (but not always) of lower potency at the target receptor thanthe species to which they are degraded. Pro-drugs are particularlyuseful when the desired species has chemical or physical propertieswhich make its administration difficult or inefficient. For example, thedesired species may be only poorly soluble, it may be poorly transportedacross the mucosal epithelium, or it may have an undesirably shortplasma half-life. Further discussion of pro-drugs may be found inStella, V. J. et al, "Prodrugs", Drug Delivery Systems, pp. 112-176(1985), and Drugs, 29, pp. 445-473 (1985).

Pro-drug forms of the pharmacologically-active compounds of theinvention include compounds according to formula (I) in which Y and/or Zinclude an esterified or amidated acid group.

The term "hydrocarbyl", as used herein, refers to monovalent groupsconsisting of carbon and hydrogen. Hydrocarbyl groups thus includealkyl, alkenyl, and alkynyl groups (in both straight and branched chainforms), cycloalkyl (including polycycloalkyl), cycloalkenyl, and arylgroups, and combinations of the foregoing, such as alkylaryl,alkenylaryl, alkynylaryl, cycloalkylaryl, and cycloalkenylaryl groups,

A "carbocyclic" group, as the term is used herein, comprises one or moreclosed chains or rings, which consist entirely of carbon atoms. Includedin such groups are alicyclic groups (such as cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and adamantyl), groups containing both alkyl andcycloalkyl moieties (such as methyl adamantyl), and aromatic groups(such as phenyl, naphthyl, indanyl, fluorenyl,(1,2,3,4)-tetrahydronaphthyl, indenyl and isoindenyl).

The term "aryl" is used herein to refer to aromatic carbocyclic groups,including those mentioned above.

A "heterocyclic" group comprises one or more closed chains or ringswhich have at least one atom other than carbon in the closed chain orring. Examples include benzimidazolyl, thienyl, furanyl, pyrrolyl,imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, pyrrolinyl,pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolindinyl,tetrahydrofuranyl, pyranyl, pyronyl, pyridyl, pyrazinyl, pyridazinyl,piperidyl, piperazinyl, morpholinyl, thionaphthyl, benzofuranyl,isobenzofuryl, indolyl, oxyindolyl, isoindolyl, indazolyl, indolinyl,7-azaindolyl, isoindazolyl, benzopyranyl, coumarinyl, isocoumarinyl,quinolyl, isoquinolyl, naphthridinyl, cinnolinyl, quinazolinyl,pyridopyridyl, benzoxazinyl, quinoxadinyl, chromenyl, chromanyl,isochromanyl and carbolinyl.

The term "halogen", as used herein, refers to any of fluorine, chlorine,bromine and iodine. Most usually, however, halogen substituents in thecompounds of the invention are chlorine or fluorine substituents.

Preferably, m and n are both O. However, when m and n are not both 0, R₃and R₄ are preferably selected from halo, hydroxy, amino, nitro, cyano,sulphamoyl, C₁ to C₃ alkyl and C₁ and C₃ alkoxy. As mentioned above,when m or n is 2 or more, each R₃ and R₄ group is independent of theothers. For example, the compounds of the invention may include twodifferent R₃ groups.

Particularly preferred groups for R₅ and R₆ are hydrogen and the groupsjust recited for R₃, and especially hydrogen, methyl and fluoro.

When reference is made herein to a "substituted" aromatic group, thesubstituents will generally be from 1 to 3 in number (and more usually 1or 2 in number), and generally selected from the groups recited abovefor R₃. However, halo substituents may be up to 5 in number.

An "esterified" carboxy group, as the term is used herein, is preferablyof the form --COOR₁₆, wherein R₁₆ is C₁ to C₅ alkyl, phenyl, substitutedphenyl, benzyl, substituted benzyl, heteroaryl or one of the following:##STR6##

Most commonly, R₁₆ is C₁ to C₅ alkyl, benzyl or substituted benzyl, andparticularly C₁ C₅ alkyl. Similarly, an "amidated " carboxy group ispreferably of the form --CONR₁₇ R₁₈ wherein R₁₇ is H, C₁ to C₅ alkyl,phenyl, substituted phenyl, benzyl or substituted benzyl, and R₁₈ is--OH or one of the groups just recited for R₁₇.

In the case of the group T, preferred amidated carboxy groups take theform --CONR₁₇ R₁₈ (wherein R₁₇ and R₁₈ are as defined above) or ##STR7##wherein R₁₇ is as defined above, R₁₉ and R₂₀ are independently H ormethyl, or R₁₉ and R₂₀ (together with the carbon atom to which they areattached) for a 3- to 7-membered carbocyclic group, J is --OH, --O--R₁₆or --NHR₁₈, wherein R₁₆ and R₁₈ are as defined above, and x is 0 to 3.

When R₁₁ and R₁₂ are linked to form a ring, such ring will generally besaturated, and usually also carbocyclic. Similarly, when Q' and R₁₂ arelinked to form a ring, this will also usually be saturated andcarbocyclic.

Exemplary carbocyclic and heterocyclic groups which may form the group Uinclude: ##STR8## wherein R₂₁ is as defined above for R₃, and h is from0 to 3, and ##STR9## wherein P is H or --COOR₂₂, in which R₂₂ is asdefined above for R₁₇.

In a preferred embodiment, Z is --NH₂, --O--R₉ or ##STR10## wherein i isfrom 0 to 4, j is from 0 to 3, R₂₃ and R₂₄ are independently H ormethyl, or R₂₃ and R₂₄ together form a group of the formula --(CH₂)_(k)--V'--CH₂ -- (wherein V' is --CH₂ --, --CHOH-- or --C(O)--, and k is 0to 2). Most commonly, i is 0 or 1 and j is 0 to 2.

When W is sulphinyl, Y is preferably R₇ --NH--.

Preferably, R₇ is C₆ to C₈ straight or branched chain alkyl orcycloalkyl, or R₂₅ --(CH₂)_(p) --, wherein R₂₅ is selected from phenyl,1-naphthyl, 2-naphthyl, indolyl, norbornyl, 1-adamantyl, 2-adamantyl,cyclohexyl or cycloheptyl, and p is from 0 to 3.

Most preferably, the compounds of the invention are of the formula##STR11## wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₁₂ and U are asdefined above,

R₂₆ is H or C₁ to C₃ alkyl, and

R₂₇ is ##STR12## (wherein R₂₈ is H or C₁ to C₃ alkyl, R₂₉ is --CO₂ H ortetrazolyl, R₃₀ is H, --CO₂ H, tetrazolyl, --CH₂ OH, --CO₂ Me or--CONH₂, and y is from 0 to 2).

Pharmaceutically acceptable salts of the acidic compounds of theinvention include salts with alkali metals and alkaline earth metals,such as sodium, potassium, calcium and magnesium, and salts with organicbases. Suitable organic bases include amines such asN-methyl-D-glucamine.

Pharmaceutically acceptable salts of the basic compounds of theinvention include salts derived from organic or inorganic acids.Suitable acids include hydrochloric acid, phosphoric acid, oxalic acid,maleic acid, succinic acid and citric acid.

The compounds of the invention exist in various enantiomeric anddiastereomeric forms as a result of the asymmetric carbon atoms to whichW and X are attached. It will be understood that the inventioncomprehends the different enantiomers and diastereomers in isolationfrom each other, as well as mixtures of enantiomers and diastereomers.Also, the structural formulae herein show the groups W and X arrangedcis to each other, but it will be appreciated that the inventionincludes the corresponding trans isomers.

Compounds according to the present invention in which W is a carbonylgroup, X is carbonyl or sulphonyl, and Z is OH may conveniently be madeby the process depicted in Reaction Scheme A. ##STR13##

In this scheme, anthracene or an anthracene derivative (1) is reactedwith the acid anhydride (2) in a Diels-Alder reaction. The reactants areconveniently refluxed together in a suitable solvent such as toluene toform the adduct (3). In some cases, it may be appropriate to conduct thereaction at elevated pressure and/or in the presence of a Lewis acidcatalyst. The adduct (3) is then reacted with a compound of the formulaYH (ie. either an alcohol or an amine) to form the acid compound (4). IfYH is an amine, the reaction is suitably carried out in a solvent suchas THF in the presence of a catalytic amount of DMAP. If YH is analcohol, the reaction may be conducted in pyridine at elevatedtemperature.

The invention therefore also provides a method of making compoundswherein W is carbonyl and X is carbonyl or sulphonyl, said methodincluding the step of reacting a compound of the formula ##STR14## witha compound of formula YH.

The equivalent trans adducts can be prepared using a suitablydifferentiated fumaric acid (e.g. the mono methyl mono benzyl diester),which, after addition to anthracene or an anthracene derivative (1),allows independent elaboration of the two sidechains.

Compounds in which Z is other than OH may of course be made from theacid compound (4) by conventional esterification or amidation reactions.Suitable amidation methods are described in detail in "The Peptides,Vol. 1", Gross and Meinenhofer, Eds., Academic Press, New York, 1979.These include the carbodiimide method (using, for example,1,3-dicyclohexylcarbodiimide DCC! or1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride EDCI!, andoptionally an additive such as 1-hydroxybenzotriazole HOBT! to preventracemization), the azide method, the mixed anhydride method, thesymmetrical anhydride method, the acid chloride method, the use of bis(2-oxo-3-oxazolidinyl) phosphinic chloride BOP-Cl!, the use of PyBOP orPyBrOP, the use of the isopropenylsuccinimido carbonate method and theactive ester method (using, for example, N-hydroxysuccinimide esters,4-nitrophenyl esters or 2,4,5-trichlorophenol esters).

The coupling reactions are generally conducted under an inertatmosphere, such as an atmosphere of nitrogen or argon. Suitablesolvents for the reactants include methylene chloride, tetrahydrofuranTHF!, dimethoxyethane DME! and dimethylformamide DMF!.

When both W and X are carbonyl, and Z is other than OH, it is of coursepossible to open the adduct (3) by reacting it with a compound of theformula ZH (suitably protected, if necessary), rather than YH, and thenesterifying or amidating the free carboxyl group of the resultingcompound using YH.

A procedure analogous to that shown in reaction scheme A may also beused as the basis for preparing the compounds of the invention in whichW is sulphonyl and Y is R₇ --O--, as depicted in reaction scheme Bbelow: ##STR15##

In this case, the Diels-Alder adduct (6) is opened with an alcohol suchas benzyl alcohol (represented as QOH), so that product (7) is thecorresponding sulphonyl ester. The free carboxylic acid group of thissulphonyl ester may then be esterified by conventional methods, followedby hydrogenolysis of the product (8) to yield the desired sulphonic acidcarboxylic ester (9).

The compounds of the invention in which W is sulphonyl and Y is R₇--NH-- may be prepared by analogous means, in which compound (7) isamidated (rather than esterified) prior to hydrogenolysis.Alternatively, a process such as is depicted in reaction scheme C may beemployed: ##STR16##

In this scheme, anthracene or an anthracene derivative (1) is reactedwith the N-protected compound (10) in a Diels-Alder reaction analogousto that of the first step in reaction scheme A. The deprotected productDiels-Alder Adduct (11) is then reacted with a compound of the formulaR₇ -Hal (wherein Hal represents a halogen atom) to form compound (12).The N-containing ring may then be opened using an alkoxide (eg. sodiummethoxide in methanol) to produce the target compound (13).

The invention therefore also provides a method of making compoundswherein W is sulphonyl and Y is R₇ --NH--, said method comprising thestep of reacting a compound of the formula ##STR17## with a compound ofthe formula R₇ -Hal, and then reacting the product with an alkoxide.

Compounds of the invention wherein W or X is a sulphinyl group mayconveniently be prepared by the route shown in reaction scheme D:##STR18##

Reaction scheme D is analogous to reaction scheme C, except that thesulphinyl analogue of compound (10) is used in the Diels-Alder reaction,to yield the sulphinyl analogue of adduct (12). This can then be openedboth ways to give on the one hand the sulphinamide acid alkyl ester(17), and on the other the sulphinic acid amide (18). The freesulphinamide acid can of course be obtained from the alkyl ester (12) byconventional methods.

Accordingly, the invention also provides a method of making compoundswherein W or X is sulphinyl, said method comprising the step of reactinga compound of the formula: ##STR19## with a compound of the formula R₇-Hal, and then reacting the product with an alkoxide.

While reaction schemes C and D above led to the free sulphonic orsulphinic acid compounds, it will be appreciated that the correspondingester or amide derivatives can be prepared from the free acid compoundsby conventional methods. Most usually, coupling of the sulphonic orsulphinic acid compounds will be via the corresponding sulphonic orsulphinic acid chlorides.

Pharmaceutically acceptable salts of the acidic or basic compounds ofthe invention can of course be made by conventional procedures, such asby reacting the free base or acid with at least a stoichiometric amountof the desired salt-forming acid or base.

The compounds of the invention can be administered by oral or parenteralroutes, including intravenous, intramuscular, intraperitoneal,subcutaneous, rectal and topical administration.

For oral administration, the compounds of the invention will generallybe provided in the form of tablets or capsules or as an aqueous solutionor suspension.

Tablets for oral use may include the active ingredient mixed withpharmaceutically acceptable excipients such as inert diluents,disintegrating agents, binding agents, lubricating agents, sweeteningagents, flavouring agents, colouring agents and preservatives. Suitableinert diluents include sodium and calcium carbonate, sodium and calciumphosphate, and lactose, while corn starch an alginic acid are suitabledisintegrating agents. Binding agents may include starch and gelatin,while the lubricating agent, if present, will generally be magnesiumstearate, stearic acid or talc. If desired, the tablets may be coatedwith a material such as glyceryl monostearate or glyceryl distearate, todelay absorption in the gastrointestinal tract.

Capsules for oral use include hard gelatin capsules in which the activeingredient is mixed with a solid diluent, and soft gelatin capsuleswherein the active ingredient is mixed with water or an oil such aspeanut oil, liquid paraffin or olive oil.

For intramuscular, intraperitoneal, subcutaneous and intravenous use,the compounds of the invention will generally be provided in sterileaqueous solutions or suspensions, buffered to an appropriate pH andisotonicity. Suitable aqueous vehicles include Ringer's solution andisotonic sodium chloride. Aqueous suspensions according to the inventionmay include suspending agents such as cellulose derivatives, sodiumalginate, polyvinylpyrrolidone and gum tragacanth, and a wetting agentsuch as lecithin. Suitable preservatives for aqueous suspensions includeethyl and n-propyl p-hydroxybenzoate.

Effective doses of the compounds of the present invention may beascertained by conventional methods. The specific dosage level requiredfor any particular patient will depend on a number of factors, includingthe severity of the condition being treated and the weight of thepatient. In general, however, the daily dose (whether administered as asingle dose or as divided doses) will be in the range 0.001 to 5000 mgper day, more usually from 1 to 1000 mg per day, and most usually from10 to 200 mg per day. Expressed as dosage per unit body weight, atypical dose will be between 0.01 μg/kg and 50 mg/kg, especially between10 μg/kg and 10 mg/kg, eg. between 100 μg/kg and 2 mg/kg.

EXAMPLE 1

Preparation of(±)-cis-8-(3-phenylpropylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane-7-carboxylic acid

a. 2,3,5,6-dibenzobicyclo 2.2.2!octane-7,8-dicarboxylic acid anhydride

Anthracene (8.9 g, 0.05 mol) and maleic anhydride (4.9 g, 0.05 mol) wererefluxed for 3 h in toluene (200 ml). Upon cooling, the title compoundwas obtained as white crystals which were isolated by filtration (10.2 g74%).

b. (±)-cis-8-(3-phenylpropylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane-7-carboxylic acid

2,3,5,6-dibenzobicyclo 2.2.2!octane-7,8-dicarboxylic acid anhydride (107mg, 0.39 mmol) and 1-phenyl-3-propylamine (55 mg, 0.4 mmol) weredissolved in dry THF (5 ml) and DMAP (2 mg) was introduced. The mixturewas stirred at room temperature overnight during which time a thickwhite precipitate formed. The solid was filtered off, washed with THFand dried to give the title compound (100 mg 62%), mp 190°-1°, found: C,78.82; H, 5.99; N, 3.40. C₂₇ H₂₅ NO₃ requires C, 78.81; H, 6.12; N,3.38%

EXAMPLE 2

Preparation of(±)-cis-8-(2-(3-indolyl)ethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane-7-carboxylic acid

The compound was prepared essentially as in example 1 except thattryptamine was used instead of 1-phenyl-3-propylamine in step b. Yield84%, m.p. 137°-8°, found: C, 74.13; H, 6.12; N, 5.73. C₂₈ H₂₄ N₂ O₃. 0.7H₂ O. 0.6 THF requires C, 74.16; H, 6.18; N, 5.69%

EXAMPLE 3

Preparation of(±)-cis-8-(phenylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane-7-carboxylic acid

The compound was prepared essentially as in example 1 except thatbenzylamine was used instead of 1-phenyl-3-propylamine in step b. Yield27%, m.p. 194°-5°, found: C, 77.35; H, 5.97; N, 3.36. C₂₅ H₂₁ NO₃. 0.5THF requires C, 77.30; H, 6.18; N, 3.34%

EXAMPLE 4

Preparation of(±)-cis-8-(1-naphthylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane-7-carboxylic acid

The compound was prepared essentially as in example 1 except that1-naphthylmethylamine was used instead of 1-phenyl-3-propylamine in stepb. Yield 35%, m.p. 135°-7°, found: C, 78.37; H, 6.07; N, 2.98. C₂₉ H₂₃NO₃. 1.0 THF requires C, 78.39; H, 6.18; N, 2.77%

EXAMPLE 5

Preparation of(±)-cis-8-(2-naphthylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane-7-carboxylic acid

The compound was prepared essentially as in example 1 except that2-naphtylmethylamine was used instead of 1-phenyl-3-propylamine in stepb. Yield 35%, m.p. 247°-8°, found: C, 80.46; H, 5.03; N, 3.32. C₂₉ H₂₃NO₃ requires C, 80.46; H, 5.03; N, 3.23%

EXAMPLE 6

Preparation of(±)-cis-8-(2-norbornylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane-7-carboxylic acid

The compound was prepared essentially as in example 1 except that2-norbornylmethylamine was used instead of 1-phenyl-3-propylamine instep b. Yield 24%, m.p. 127°-9°, found: C, 74.93; H, 7.07; N, 3.76. C₂₆H₂₇ NO₃. 0.75 H₂ O requires C, 75.24; H, 6.92; N, 3.38%

EXAMPLE 7

Preparation of (±)-cis-8-(hexylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane-7-carboxylic acid

The compound was prepared essentially as in example 1 except thathexylamine (2eq) was used instead of 1-phenyl-3-propylamine in step b.and the product was precipitated with 2M HCl and then filtered andwashed with water. Yield 91%, m.p. 174°-6°, found: C, 76.52; H, 7.24; N,3.98. C₂₄ H₂₇ NO₃ requires C, 76.36; H, 7.21; N, 3.71%

EXAMPLE 8

Preparation of (±)-cis-8-(octylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane-7-carboxylic acid

The compound was prepared essentially as in example 7 except thatoctylamine was used instead of hexylamine. Yield 89%, m.p. 116°-8°,found: C, 76.83; H, 7.70; N, 3.58. C₂₆ H₃₁ NO₃ requires C, 77.01; H,7.71; N, 3.45%

EXAMPLE 9

Preparation of(±)-cis-8-(cyclohexylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane-7-carboxylic acid

The compound was prepared essentially as in example 7 except thatcyclohexylmethylamine was used instead of hexylamine. Yield 93%, m.p.185°-7°, found: C, 76.88; H, 7.09; N, 3.69. C₂₅ H₂₇ NO₃ requires C,77.09; H, 6.99; N, 3.60%

EXAMPLE 10

Preparation of(±)-cis-8-(3,3-dimethylbutylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane-7-carboxylic acid

The compound was prepared essentially as in example 7 except that3,3-dimethylbutylamine was used instead of hexylamine. Yield 25%, m.p.128°-30°, found: C, 74,56; H, 7.22; N, 3.29. C₂₄ H₂₇ NO₃. 0.2 H₂ Orequires C, 75.64; H, 7.25; N, 3.68%

EXAMPLE 11

Preparation of(±)-cis-8-(1-adamantylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane-7-carboxylic acid

2,3,5,6-dibenzobicyclo 2.2.2!octane-7,8-dicarboxylic acid anhydride(prepared in example 1 step a) (276 mg, 1.0 mmol) was dissolved in THF(5 ml) and 1-adamantamine (215 mg, 1.4 mmole) was added followed bytriethylamine (0.16 ml). The solution was heated at a gentle reflux for1.5 h and the clear solution on cooling was poured onto 2M HCl (20 ml).The resulting gummy solid was extracted with dichloromethane (10 ml) andthe organic layer was dried, filtered and evaporated. The residue wastaken up in methanol (5 ml) and diluted with water (5 ml) to precipitatea white solid. This was filtered off and dried. The product (230 mg,54%), m.p. 234°-5°, found: C, 76.14; H, 6.72; N, 3.10. C₂₈ H₂₉ NO₃.0.75H₂ O requires C, 76.25; H, 6.97; N, 3.17%

EXAMPLE 12

Preparation of(±)-cis-8-(2-(1-adamantyl)ethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane-7-carboxylic acid

The compound was prepared essentially as in example 11 except that1-adamantylethylamine was used instead of 1-adamantylamine. Yield 26%,m.p. 138°-40°, found: C, 77.31; H, 7.21; N, 2.70. C₃₀ H₃₃ NO₃. 0.6 H₂ Orequires C, 77.26; H, 7.39; N, 3.00%

EXAMPLE 13

Preparation of(±)-cis-8-(-1-adamantylmethyloxycarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane-7-carboxylic acid

2,3,5,6-dibenzobicyclo 2.2.2!octane-7,8-dicarboxylic acid anhydride(prepared in example 1 step a) (276 mg, 1.0 mmol) and1-adamantanemethanol (166 mg, 1.0 mmol) were heated together in pyridine(2 ml) at 100° for 4 h. After cooling the solution was poured onto 2MHCl and extracted with dichloromethane (20 ml). The solution was driedfiltered and evaporated to leave a white residue which was furtherpurified by column chromatography (silica dichloromethane/ethylacetate/methanol 9:1:0.5 as eluent). The product was further trituratedwith hexane to leave the title compound (110 mg, 25%), m.p. 165°, foundC, 77.14; H, 6.88. C₂₉ H₃₀ O₄.0.5 H₂ O requires C, 77.13; H, 6.19%

EXAMPLE 14

Preparation of(±)-cis-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane-7-carboxylic acid

2,3,5,6-dibenzobicyclo 2.2.2!octane-7,8-dicarboxylic acid anhydride(prepared in example 1 step a) (276 mg, 1.0 mmol) and1-adamantanemethylamine (182 mg, 1.1 mmol) were dissolved in dry THF (5ml) and refluxed for 1 h. A thick white precipitate was formed and thiswas isolated by filtration and washed with THF to leave the titlecompound (320 mg, 72%), m.p. 237°-9°, found: C,78.76; H, 7.18; N, 3.33.C₂₉ H₃₁ NO₃ requires C, 78.88; H, 7.08; N, 3.17% The compound wasfurther characterised as the N-methyl-D-glucamine salt found: C, 63.48;H, 7.61; N, 3.79. C₃₆ H₄₈ N₂ O₈. 2.5H₂ O requires C, 63.42; H, 7.83; N,4.11%

EXAMPLE 15

Preparation of(±)-cis-7-(methoxycarbonylmethylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane.

(±)-cis-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane-7-carboxylic acid prepared as in example 14 (441 mg, 1.0mmol) was dissolved in warm DMF (5 ml) and then the solution was cooledto 0°. N-hydroxysuccinimide (115 mg, 1.0 mmol) was added followed byDCCI (206 mg, 1.0 mmol). The reaction was allowed to warm to roomtemperature and stirred overnight. The white precipitate was removed byfiltration. Triethylamine (0.2 ml) was added to the filtrate followed byglycine methyl ester hydrochloride (125 mg, 1 mmol) and the reactionmixture was stirred for a further 24 h. The reaction mixture was pouredonto a mixture of 2M HCl and ice. The white precipitate was isolated byfiltration and washed well with water and dried. The solid was taken upin ethyl acetate (20 ml) and filtered through celite. The residue onevaporation was triturated with methanol leaving a white crystallinesolid (125 mg, 24%), m.p. 209°-11°, found C, 74.16; H, 7.14; N, 5.53 C₃₂H₃₆ N₂ O₄ requires C, 74.19; H, 7.12; N, 5.40%

EXAMPLE 16

Preparation of(±)-cis-7-(carboxymethylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane

a.(±)-cis-7-(benzyloxycarbonylmethylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane

(±)-Cis-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane-7-carboxylic acid (prepared as in example 14) (440 mg, 1mmole) and PyBOP (520 mg, 1 mmole) were taken up in dry dichloromethane(15 ml) and Hunigs base (0.52 ml, 3 mmole) was added. The reactionmixture was stirred under an atmosphere of dry argon for 1 h. glycinebenzyl ester 4-toluenesulphonic acid salt (340 mg, 1 mmole) was addedand the mixture stirred overnight. The organic layer was washed with 5%potassium hydrogensulphate (15 ml), sodium hydrogencarbonate (15 ml) andsaturated brine (15 ml). It was then dried, filtered and evaporated toleave the crude title compound which was further purified by columnchromatography on silica using 80% ethyl acetate and 20% hexane aseluent. The title compound (510 mg, 87%) was isolated as a white solid,m.p. 130°-3°

b.(±)-cis-7-(carboxymethylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane

The product of step a (350 mg, 0.59 mmole) was dissolved in methanol (20ml) and 10% palladium on charcoal (100 mg) was added. The mixture wasstirred under an atmosphere of hydrogen for 3 h. The product wasfiltered through celite and on evaporation yielded the title compound(0.30 g, 100%). The product was characterised and tested as theN-methyl-D-glucamine salt, m.p. 110°-2°, found: C, 63.42; H, 7.55; N,5.66. C₃₈ H₅₁ N₃ O₉. 1.5 H₂ O requires C, 63.42; H, 7.68; N, 5.66%.

EXAMPLE 17

Preparation of methyl(±)-cis-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane-7-carboxylate

2,3,5,6-dibenzobicyclo 2.2.2!octane-7,8-dicarboxylic acid anhydride(prepared as in example 1 step a) (2.76 g, 6.0 mmol), methanol (0.41 ml)and DMAP (20 mg) were stirred in pyridine (5 ml). The solution wasstirred and refluxed for 4 h, poured onto 2M HCl (50 ml) and extractedwith dichloromethane. The organic layer was washed with mor 2M HCl andthen water. The solution was dried filtered and evaporated to yield thecrude monoester (1.7 g). This material (308 mg, 1 mmol) and1-adamantanemethylamine (181 mg, 1.0 mmol) were dissolved in drydichloromethane (10 ml) and diisopropylethylamine (0.35 ml) was addedfollowed by PyBOP (520 mg, 1 mmol). The solution was stirred at roomtemperature for 72 h. It was then evaporated and the residue taken up inethyl acetate and washed successively with 5% aqueous potassiumhydrogensulphate (3×40 ml), saturated aqueous sodium hydrogencarbonate(40 ml) and brine (40 ml). The organic layer was dried, filtered andevaporated to leave a foam that was purified by column chromatography(silica eluent 90% dichloromethane and 10% ethyl acetate). Furtherpurification was achieved by recrystallisation from methanol. Yield 200mg, 44%, m.p. 227°-30°, found: C, 79.06; H, 7.54; N, 2.94. C₃₀ H₃₃ NO₃requires C, 79.09; H, 7.30; N, 3.07%

EXAMPLE 18

Preparation of(±)-cis-8-(2-naphthylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane-7-sulphonic acid

a. Diels-Alder adduct of anthracene and 3-oxo-2,3-dihydroisothiazolone

N-t-butyl-3-oxo-2,3-dihydroisothiazolone (prepared as in Helv.Chim.Acta., 1989, 72, 1416) (200 mg, 1.1 mmol) and anthracene (178 mg, 1mmol) were suspended in dry toluene (2 ml) and a catalytic amount ofanhydrous aluminium chloride was added. The reaction mixture was stirredand refluxed overnight. On cooling a white solid separated which wasfiltered and washed successively with toluene and pentane and air dried.The solid was then taken up in ethyl acetate and washed with dilute HCland brine and finally dried and evaporated to leave a white solid (185mg, 62%)

b. Alkylation of the Diels-Alder adduct

The product from step a (312 mg, 1 mmol), anhydrous potassium carbonate(138 mg, 1 mmol) and 2-bromomethylnaphthalene (225 mg, 1 mmol) weredissolved in dry DMF (3 ml) and stirred and heated to 100° for 4 h.After cooling the solution was poured onto cold water (30 ml) and theresulting white solid filtered off and dried in an oven. The solid wastriturated with hexane/toluene/ethanol 9:9:2 and the solid wasrecrystallised from ethanol (178 mg, 39%), m.p. 184°-5°

c. 8-(2-naphthylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane-7-sulphonic acid

Sodium (16 mg, 0.7 mmol) was dissolved in methanol (5 ml) and theproduct from step b was added (225 mg, 0.5 mmol). The reaction wasstirred and refluxed for 1 h. The reaction mixture was cooled andacidified with concentrated HCl. The reaction mixture was thenevaporated and the residue partitioned between water and ethyl acetate.The organic layer was dried and evaporated. The product wasrecrystallised from chloroform. Yield 152 mg, 32%, m.p. 245°-7° found:C, 68.74; H, 4.88; N, 2.83. C₂₈ H₂₃ NO₄ S. 1.0 H₂ O requires C, 68.97;H, 5.16; N, 2.87%

EXAMPLE 19

Preparation of(±)-cis-8-(phenylmethylaminocarbonyl)2,3,5,6-dibenzobicyclo2.2.2!octane-7-sulphonic acid

This was prepared essentially as in example 18 using benzyl bromide instep b instead of 2-bromomethylnaphthalene m.p. 245°-7° found: C,68.764; H, 4.81; N, 3.19. C₂₄ H₂₁ NO₄ S requires C, 68.72; H, 5.05; N,3.34%

EXAMPLE 20

Preparation of(±)-cis-8-(2-naphthylmethylaminosulphonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane-7-carboxylic acid

a. Diels-Alder adduct of anthracene and β-sulphoacrylic anhydride

β-sulphoacrylic anhydride (prepared as in J.A.C.S. 1962, 84, 653) (184mg, 1.0 mmol) and anthracene (178 mg, 1 mmol) were suspended in drytoluene (6 ml) and refluxed under an atmosphere of dry nitrogen for 3 h.The reaction mixture was decanted from a small amount of tarry residueand cooled in ice. White crystals that separated were filtered off andwashed with a little hexane and dried. Yield 163 mg, 52%

b. (±)-cis-8-(2-naphthylmethylaminosulphonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane-7-carboxylic acid

The Adduct from step a (207 mg, 0.66 mmole) and 2-naphthylmethylamine(209 mg, 1.33 mmol) were dissolved in dry THF (5 ml) and DMAP (5 mg) wasadded. The solution was stirred at room temperature overnight andevaporated to dryness. The residue was taken up in methanol and waterand stirred with Amberlite

IR-120(plus) resin, filtered and evaporated. The residue was trituratedwith ether, to yield the title compound 215 mg, 68% m.p. 212-15 found:C, 69.78; H, 4.98; N, 2.98. C₂₈ H₂₃ NO₄ S. 0.7 H₂ O requires C, 69.75;H, 5.10; N, 2.91%

EXAMPLE 21

Preparation of(±)-cis-8-(2-(3-indolyl)ethylaminosulphonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane-7-carboxylic acid

This was prepared essentially as in example 20 but using tryptamineinstead of 2-naphthylmethylamine in step b, m.p.>220° found: C, 68.87;H, 5.17; N, 6.07. C₂₇ H₂₄ N₂ O₄ S requires C, 68.63; H, 5.12; N, 5.92%

EXAMPLE 22

Preparation of(±)-cis-8-(1-adamantylmethylaminosulphonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane-7-carboxylic acid

This was prepared essentially as in example 21 but using1-adamantylmethylamine instead of 2-naphthylmethylamine in step b, m.p.135°-40° found: C, 69.90; H, 6.49; N, 2.68. C₂₈ H₃₁ NO₄ S. 0.2 H₂ Orequires C, 69.89; H, 6.58; N, 2.91%

EXAMPLE 23

Preparation ofcis-7-(1-R-carboxy-ethylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

(±)-cis-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane-7-carboxylic acid (prepared as in example 14) (440 mg, 1mmol) was dissolved by warming in dry DMF (10 ml).Isopropenylsuccinimido carbonate (200 mg, 1 mmole) was then added atroom temperature. A catalytic amount of DMAP was added and the reagentsstirred for 4 h. Triethylamine (0.168 ml, 1.2 mmole) was added followedby D-alanine (100 mg, 1.1 mmole) and the reaction left to stir at roomtemperature for 60 h. The reaction mixture was poured onto 2N HCl andthe white precipitate so formed was isolated by filtration. The solidwas further purified by column chromatography (silica, dichloromethaneto 90% dichloromethane and 10% methanol) to leave the title compound (50mg). The compound was characterised and tested as theN-methyl-D-glucamine salt m.p. 128°-30°, found: C, 61.98; H, 7.42; N,5.85. C₃₉ H₅₃ N₃ O₉. 2.4 H₂ O requires C, 62.32; H, 7.75; N, 5.59%

EXAMPLE 24

Preparation ofcis-(±)-7-(2-methoxycarbonylethylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane

This was prepared essentially as in example 23 using beta-alanine methylester instead of D-alanine, m.p. 207°, found: C, 74.98; H, 7.46; N,5.27. C₃₃ H₃₈ N₂ O₄ requires C, 75.26; H, 7.27; N, 5.32%

EXAMPLE 25

Preparation ofcis-7-(1-S-methoxycarbonyl-ethylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

(±)-cis-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane-7-carboxylic acid (prepared as in example 14) (440 mg, 1mmole) and PyBOP (520 mg, 1 mmole) were taken up in dry dichloromethane(15 ml) and Hunigs base (0.52 ml, 3 mmole) was added. The reactionmixture was stirred under an atmosphere of dry argon for 1 h. L-alaninemethyl ester hydrochloride (140 mg, 1 mmole) was added and the mixturestirred overnight. The organic layer was washed with 5% potassiumhydrogensulphate (15 ml), sodium hydrogencarbonate (15 ml) and saturatedbrine (15 ml). It was then dried, filtered and evaporated to leave thecrude title compound which was further purified by column chromatographyon silica using 80% ethyl acetate and 20% hexane as eluent. The titlecompound (300 mg, 57%) was isolated as a white solid, m.p. 107°, found:C, 75.33; H, 7.25; N, 5.16. C₃₃ H₃₈ N₂ O₄ requires C, 75.26; H, 7.27; N,5.32%

EXAMPLE 26

Preparation ofcis-7-(1-S-methoxycarbonyl-ethylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereomer A

The compound of example 25 was separated into its componentdiastereomers by preparative HPLC using a silica phase column and 50%ethyl acetate and 50% hexane as eluant. The title compound diastereomerA had a retention time of 18.4 minutes and was isolated as a whitepowder, m.p.95°-100°, α!^(D) =-10.5° (c=1.66 in methanol), found: C,75.32; H, 7.14; N, 5.33. C₃₃ H₃₈ N₂ O₄ requires C, 75.26; H, 7.27; N,5.32%

EXAMPLE 27

Preparation ofcis-7-(1-S-methoxycarbonyl-ethylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereomer B

The compound of this example was the second diastereomer isolated by theHPLC technique described in example 26. The title compound diastereomerB had a retention time of 21.7 minutes and was isolated as a whitepowder, m.p.75°-85°, α!^(D) =+3.8° (c=1.57 in methanol), found: C,73.41; H, 7.37; N, 5.20. C₃₃ H₃₈ N₂ O₄. 0.73 H₂ O requires C, 73.42; H,7.37; N, 5.20%

EXAMPLE 28

Preparation ofcis-7-(1-R-methoxycarbonyl-ethylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The reaction was performed essentially as in example 25 but usingD-alanine methyl ester hydrochloride instead of the L-isomer. The titlecompound (300 mg, 57%) was isolated as a white solid, m.p. 113°-5°,found: C, 74.41; H, 7.42; N, 5.14. C₃₃ H₃₈ N₂ O₄.0.33 H₂ O requires C,74.41; H, 7.32; N, 5.26%

EXAMPLE 29

Preparation ofcis-(±)-7-(2-benzyloxycarbonyl-ethylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane

The reaction was performed essentially as in example 25 but using thebenzyl ester of beta alanine instead of L-alanine methyl esterhydrochloride. Yield 70%, m.p. 77°-8°, found: C, 76.67; H, 7.04; N,4.52. C₃₉ H₄₂ N₂ O₄.0.43 H₂ O requires C, 76.73; H, 7.08; N, 4.59%

EXAMPLE 30

Preparation ofcis-(±)-7-(2-carboxy-ethylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane

The product of example 29 (370 mg, 0.6 mmole) was dissolved in ethanol(20 ml) and 10% palladium on charcoal (100 mg) was added. The mixturewas stirred under an atmosphere of hydrogen overnight. The product wasfiltered through celite and on evaporation yielded the title compound,56%. The product was characterised and tested as theN-methyl-D-glucamine salt, m.p. 75°-8°, found: C, 62.54; H, 7.94; N,5.31. C₃₉ H₅₃ N₃ O₉. 2.44 H₂ O requires C, 62.31; H, 7.76; N, 5.59%

EXAMPLE 31

Preparation ofcis-7-(1-S-aminocarbonyl-ethylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The reaction was performed essentially as in example 25 but usingL-alaninamide hydrochloride instead of the L-alanine methyl esterhydrochloride. Yield 81%, m.p. 175°-185°, α!^(D) =-6.5° (c=1 inmethanol), found: C, 73.13; H, 7.53; N, 7.95. C₃₂ H₃₇ N₃ O₃. 0.76 H₂ Orequires C, 73.16; H, 7.39; N, 8.00%

EXAMPLE 32

Preparation ofcis-7-(1-S-hydroxymethyl)-ethylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The reaction was performed essentially as in example 25 but usingL-alaninol instead of the L-alanine methyl ester hydrochloride. Yield76%, m.p. 115°-120°, α!^(D) =-4.0° (c=1 in methanol), found: C, 73.09;H, 7.82; N, 5.32. C₃₂ H₃₈ N₂ O₃. 1.5 H₂ O requires C, 73.14; H, 7.86; N,5.33%

EXAMPLE 33

Preparation ofcis-7-(1-S-benzyloxycarbonyl-ethylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereomer A

The reaction was performed essentially as in example 25 but using theL-alanine benzyl ester of instead of L-alanine methyl esterhydrochloride. Overall yield 62%, The two diastereomers were separatedby column chromatography (silica eluant 93% dichloromethane and 7% ethylacetate). The less polar isomer has been designated diastereomer A, thetitle compound, Retention time HPLC silica 50% hexane and 50% ethylacetate 7.9 min, m.p. 92°-4°, α!^(D) =-5.0° (c=1 in chloroform), found:C, 75.49; H, 7.12; N, 4.40. C₃₉ H₄₂ N₂ O₄.1.0 H₂ O requires C, 75.39; H,7.15; N, 4.51%

EXAMPLE 34

Preparation ofcis-7-(1-S-benzyloxycarbonyl-ethylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereomer B

The more polar isomer from the chromatographic separation outlined inexample 33 was designated diastereomer B, Retention time HPLC silica 50%hexane and 50% ethyl acetate 10.9 min, m.p. 90°-5°, α!^(D) =-1.0° (c=1in chloroform), found: C, 77.66; H, 7.24; N, 4.41. C₃₉ H₄₂ N₂ O₄requires C, 77.71; H, 7.02; N, 4.65%

EXAMPLE 35

Preparation ofcis-7-(1-S-carboxyethylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereomer A

The compound was prepared essentially as described in example 30 butusing the product of example 33 instead ofcis-(±)-7-(2-benzyloxycarbonyl-ethylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (the product of example 29) as the substrate. Yield 87%,α!^(D) =-16.0° (c=1 in methanol). The compound was further characterisedand tested as the N-methyl-D-glucamine salt, m.p. 100°-105°, found: C,60.66; H, 7.82; N, 5.74. C₃₉ H₅₃ N₃ O₉. 3.4 H₂ O requires C, 60.93; H,7.84; N, 5.47%.

EXAMPLE 36

Preparation ofcis-7-(1-S-carboxyethylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereomer B

The compound was prepared essentially as described in example 30 butusing the product of example 34 instead ofcis-(±)-7-(2-benzyloxycarbonyl-ethylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (the product of example 29) as the substrate. Yield 99%,α!^(D) =+3.5° (c=1 in methanol). The compound was further characterisedand tested as the N-methyl-D-glucamine salt, m.p. 105°-110°, found: C,61.89; H, 7.67; N, 5.72. C₃₉ H₅₃ N₃ O₉. 2.6 H₂ O requires C, 62.03; H,7.77; N, 5.57%.

EXAMPLE 37

Preparation ofendo-cis-(±)-8-(1-adamantylmethylaminocarbonyl)-2,3-benzo-5,6-(2,5-dimethoxybenzo)bicyclo2.2.2!octane-7-carboxylic acid

a. Diels-Alder adduct of 1,4-dimethoxyanthracene

Maleic anhydride (0.21 g, 2.18 mmole) and 1,4-dimethoxyanthracene (0.52g, 2.18 mmole) were dissolved in toluene (5 ml) and heated to reflux for4 h under an atmosphere of argon. The solvent was evaporated and theresidue washed with dichloromethane affording a white powder which wasrecrystallised from acetone to yield the exo adduct (140 mg), used inthe preparation of example 38. The endo adduct was obtained as a whitesolid on addition of hexane to the dichloromethane solution, which wasfiltered and dried (143 mg).

b.endo-cis-(±)-8-(1-adamantylmethylaminocarbonyl)-2,3-benzo-5,6-(2,5-dimethoxybenzo)bicyclo2.2.2!octane-7-carboxylic acid

The endo adduct (from step a) (132 mg, 0.39 mmole) was dissolved in THF(3 ml) and 1-adamantylmethylamine (70 mg, 0.39 mmole) was added. Thereaction was stirred at room temperature under an atmosphere of argonfor 15 min. The solution was evaporated and taken up in dichloromethaneand precipitated with hexane. The solution was filtered and dried,dissolved in warm ether and decanted from insoluble material. Additionof hexane, cooling and filtration gave the title compound (93 mg, 48%).The compound was characterised and tested as the N-methyl-D-glucaminesalt, m.p. 99°-103°, found: C, 61.63; H, 7.73; N, 3.92. C₃₈ H₅₂ N₂ O₁₀.2.3 H₂ O requires C, 61.76; H, 7.73; N, 3.79%.

EXAMPLE 38

Preparation ofexo-cis-(±)-8-(1-adamantylmethylaminocarbonyl)-2,3-benzo-5,6-(2,5-dimethoxybenzo)bicyclo2.2.2!octane-7-carboxylic acid

The compound was prepared essentially as in example 37 step b but usingthe exo anhydride from example 37, step a, rather than the endo isomer.Yield 88%. The compound was characterised and tested as theN-methyl-D-glucamine salt, m.p. 109°-112°, found C, 63.07; H, 7.70; N,3.71. C₃₈ H₅₂ N₂ O₁₀. 1.5 H₂ O requires C, 63.04; H, 7.66; N, 3.87%.

EXAMPLE 39

Preparation ofcis-(±)-8-(2-adamantylmethylaminocarbonyl)-2,3-benzo-5,6-(2,5-dimethoxybenzo)bicyclo2.2.2!octane-7-carboxylic acid

The compound was prepared essentially as in example 1 step b using2-adamantylmethylamine instead of 1-phenyl-3-propylamine. Yield 85%. Thecompound was characterised and tested as the N-methyl-D-glucamine salt,found: C, 67.73; H, 7.81; N, 4.41. C₃₆ H₄₈ N₂ O₈ requires C, 67.90; H,7.60; N, 4.40%.

EXAMPLE 40

Preparation ofcis-7-(1-S-dimethylaminocarbonylethylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The reaction was performed essentially as in example 25 but usingL-alanine-N,N-dimethylamide trifluoroacetate instead of the L-alaninemethyl ester hydrochloride. Yield 79%, m.p. 130°-5°, α!^(D) =-14° (c=1in methanol) found: C, 72.58; H, 7.86; N, 7.35. C₃₄ H₄₁ N₃ O₃. 1.3 H₂ Orequires C, 72.49; H, 7.81; N, 7.46%

EXAMPLE 41

Preparation ofcis-7-(1-S-methoxycarbonylethylaminocarbonyl)-8-(cyclohexylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The reaction was performed essentially as in example 25 but using(±)-cis-8-(1-cyclohexylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane-7-carboxylic acid (prepared in example 9) instead of(±)-cis-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane-7-carboxylic acid. Yield 59%, m.p. 80°-2°, found: C, 73.10;H, 7.31; N, 5.78. C₂₉ H₃₄ N₂ O₄ requires C, 73.39; H, 7.22; N, 5.90%

EXAMPLE 42

Preparation of cis-7-methoxycarbonylmethyl-(N-methyl)-aminocarbonyl!-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane

The reaction was performed essentially as in example 25 but using themethyl ester of sarcosine hydrochloride instead of the L-alanine methylester hydrochloride. Yield 74%, m.p. 185°-7°, found: C, 75.47; H, 7.33;N, 5.22. C₃₃ H₃₈ N₂ O₄ requires C, 75.26; H, 7.27; N, 5.32%

EXAMPLE 43

Preparation of cis-7-ethoxycarbonylmethyl-(N-methyl)-aminocarbonyl!-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane

The reaction was performed essentially as in example 25 but using theethyl ester of sarcosine hydrochloride instead of the L-alanine methylester hydrochloride. Yield 57%, found: C, 75.40; H, 7.51; N, 5.03. C₃₄H₄₀ N₂ O₄ requires C, 75.53; H, 7.46; N, 5.18%

EXAMPLE 44

Preparation of(±)-trans-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane-7-carboxylic acid

a. (±)-trans-8-ethoxycarbonyl-2,3,5,6-dibenzobicyclo2.2.2!octane-7-carboxylic acid

Anthracene (5 g, 28 mmol) and fumaric acid monoethyl ester (4.04 g, 28mmol) were dissolved in dioxan (50 ml) and the solution heated at refluxfor 3d. The reaction mixture was evaporated and the solid obtainedrecrystallised from hot toluene and dried (5.06 g, 56%).

b.(±)-trans-ethyl-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane-7-carboxylate

The product of step a (0.2 g, 0.62 mmol) was stirred in anhydrousbenzene (25 ml) and thionyl chloride (0.27 ml, 3.1 mmol) was added. Themixture was stirred at room temperature for 2 h. The solution wasevaporated in vacuo to leave a gum. This was taken up in drydichloromethane (25 ml) and 1-adamantylmethylamine (0.103 g, 0.62 mmol)was added followed by triethylamine (0.095 0 ml, 0.68 mmol) and themixture stirred at room temperature for 1 h. The dichloromethanesolution was washed successively with 2M hydrochloric acid, water andsaturated brine and dried, filtered and evaporated to afford acolourless solid (0.28 g, 96%).

c. (±)-trans-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane-7-carboxylic acid

The product of step b (0.28 g, 0.6 mmol) was dissolved in ethanol (20ml) and sodium hydroxide (48 mg, 1.2 mmole) was added. The reactionmixture was heated to reflux for 2 min whereupon it was diluted with 2Nhydrochloric acid, cooled to room temperature and filtered. Theprecipitated solid was washed successively with water, ethanol (2 ml),ether (10 ml) and dried (165 mg, 63%). The compound was characterisedand tested as the N-methyl-D-glucamine salt, found: C, 67.73; H, 7.62;N, 4.22. C₃₆ H₄₈ N₂ O₈ requires C, 67.90; H, 7.60; N, 4.40%.

EXAMPLE 45

Preparation of methylcis-(±)-8-(1-adamantylmethyloxycarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane-7-carboxylate

cis-(±)-8-(1-adamantylmethyloxycarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane-7-carboxylic acid prepared as in example 13 (115 mg, 0.26mmol) was dissolved in ether (10 ml) and a solution of diazomethane inether was added dropwise until a yellow colour persisted in solution.After 20 min at room temperature the reaction was quenched by dropwiseaddition of acetic acid. The reaction mixture was diluted with ether andwashed sequentially with 5% sodium hydrogencarbonate solution and brine.The organic layer was dried, filtered and evaporated to give acolourless glass. Trituration with hexane then gave the desired productas a white solid (65 mg, 55%), m.p. 186°-7°, found: C, 78.86; H, 7.06.C₃₀ H₃₂ O₄ requires C, 78.92; H, 7.06%

EXAMPLE 46

Preparation ofcis-7-(2-R-benzyloxycarbonyl-pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

(±)-cis-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane-7-carboxylic acid (prepared as in example 14) (440 mg, 1mmole) and PyBOP (520 mg, 1 mmole) were taken up in dry dichloromethane(15 ml) and Hunigs base (0.52 ml, 3 mmole) was added. The reactionmixture was stirred under an atmosphere of dry argon for 1 h. D-Prolinebenzyl ester hydrochloride (266 mg, 1.1 mmole) was added and the mixturestirred overnight. The organic layer was washed with 5% potassiumhydrogensulphate (15 ml), sodium hydrogencarbonate (15 ml) and saturatedbrine (15 ml). It was then dried, filtered and evaporated to leave thecrude title compound which was further purified by column chromatographyon silica using a gradient elution starting with 50% ethyl acetate and50% hexane going up to 80% ethyl acetate and 20% hexane. The titlecompound (580 mg, 92%) was isolated, m.p. 89°-90°, found: C, 78.14; H,7.13; N, 4.41. C₄₁ H₄₄ N₂ C₄ requires C, 78.31; H, 7.05; N, 4.45%

EXAMPLE 47

Preparation ofcis-7-(2-S-benzyloxycarbonyl-pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

This compound was prepared essentially as in example 46 using L-prolinebenzyl ester hydrochloride instead of D-proline benzyl esterhydrochloride. m.p. 91°-2°, found: C, 77.03; H, 7.12; N, 4.22. C₄₁ H₄₄N₂ O₄. 0.6 H₂ O requires C, 76.99; H, 7.12; N, 4.38%

EXAMPLE 48

Preparation ofcis-7-(2-R-carboxy-pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2!octane (mixture of diastereomers)

The product of example 46 (520 mg, 0.83 mmol) was dissolved in ethanol(20 ml) and 10% palladium on charcoal (100 mg) was added.

The reaction mixture was stirred overnight under an atmosphere ofhydrogen and then filtered through celite and evaporated to yield thetitle compound (380 mg, 86%). The compound was characterised and testedas the N-methyl-D-glucamine salt m.p. 124°-7°, found: C, 64.58; H, 7.92;N, 5.38. C₄₁ H₅₅ N₃ O₉. 1.71 H₂ O requires C, 64.40; H, 7.70; N, 5.45%

EXAMPLE 49

Preparation ofcis-7-(2-S-carboxy-pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

This compound was prepared essentially as in example 48 but using theproduct of example 47 as substrate rather than the product of example46. Yield 60% The compound was characterised and tested as theN-methyl-D-glucamine salt m.p. 98°-101°, found: C, 61.12; H, 8.11; N,5.08. C₄₁ H₅₅ N₃ O₉. 3.88 H₂ O requires C, 61.26; H, 7.87; N, 5.23%

EXAMPLE 50

Preparation ofcis-7-(2-methoxycarbonyl-pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The compound of example 46 (320 mg, 0.59 mmol) was dissolved in dioxan(10 ml) and a solution of diazomethane in ether was added dropwise untilthe colour persisted. After stirring for 1 h at room temperature aceticacid was added to quench the reaction and the solution was evaporatedand taken up in ethyl acetate. The product was then washed withsaturated sodium hydrogencarbonate solution and saturated brine. Theorganic phase was dried filtered and evaporated and the title compoundpurified on silica using 50% ethyl acetate and 50% hexane as eluent.Yield (120 mg, 37%), m.p. 112°-5°, found: C, 75.86; H, 7.43; N, 4.96.C₃₅ H₄₀ N₂ O₄ requires C, 75.86; H, 7.29; N, 5.07%

EXAMPLE 51

Preparation ofcis-7-(2-S-methoxycarbonyl-pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

This compound was prepared essentially as in example 50 using thecompound of example 47 as substrate instead of the compound of example46. Yield 43%, m.p. 104°-6°, found: C, 74.55; H, 7.43; N, 4.88. C₃₅ H₄₀N₂ O₄. 0.6 H₂ O requires C, 74.57; H, 7.37; N, 4.97%

EXAMPLE 52

Preparation of(±)-cis-7-(3-indolylethylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane

(±)-cis-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane-7-carboxylic acid (prepared as in example 14) (440 mg, 1mmole) and PyBOP (520 mg, 1 mmole) were taken up in dry dichloromethane(15 ml) and Hunigs base (0.52 ml, 3 mmole) was added. The reactionmixture was stirred under an atmosphere of dry argon for 1 h. Tryptaminehydrochloride (197 mg, 1 mmole) was added and the mixture stirredovernight. The organic layer was washed with 5% potassiumhydrogensulphate (15 ml), sodium hydrogencarbonate (15 ml) and saturatedbrine (15 ml). It was then dried, filtered and evaporated to leave thecrude title compound which was further purified by column chromatographyon silica using 15% ethyl acetate and 85% dichloromethane as eluent. Thetitle compound (432 mg, 74%) was isolated as a white solid, m.p.130°-40°, found: C, 75.92; H, 6.98; N, 7.19. C₃₉ H₄₁ N₃ O₂ requires C,76.26; H, 7.28; N, 6.84%

EXAMPLE 53

Preparation of cis-7-R-2-(3-indolyl)-1-methoxycarbonyl-ethylaminocarbonyl!-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

This compound was prepared essentially as in example 52 usingD-tryptophan methyl ester hydrochloride instead of tryptaminehydrochloride. Yield 78%, m.p. 135°-40°, found: C, 75.64; H, 6.81; N,6.09. C₄₁ H₄₃ N₃ O₄. 0.65 H₂ O requires C, 75.35; H, 6.83; N, 6.43%

EXAMPLE 54

Preparation of cis-7-2-S-(3-indolyl)-1-methoxycarbonyl-ethylaminocarbonyl!-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

This compound was prepared essentially as in example 52 usingL-tryptophan methyl ester hydrochloride instead of tryptaminehydrochloride. Yield 80%, m.p. 135°-42°, found: C, 76.55; H, 6.95; N,6.77. C₄₁ H₄₃ N₃ O₄ requires C, 76.63; H, 6.75; N, 6.55%

EXAMPLE 55

Preparation of cis-7-2-R-(3-indolyl)-1-carboxyethylaminocarbonyl!-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereomer 1

a. cis-7-2-R-(3-indolyl)-1-benzyloxycarbonyl-ethylaminocarbonyl!-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane and separation of diastereomers

The mixture of diastereomers was prepared essentially as in example 52using D-tryptophan benzyl ester trifluoroacetate salt instead oftryptamine hydrochloride. The diastereomers were separated by columnchromatography (silica 15% ethyl acetate and 85% dichloromethane) togive a 35% yield of each component.

b. cis-7-2-R-(3-indolyl)-1-carboxy-ethylaminocarbonyl!-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo-2.2.2!octane Diastereomer 1

Diastereomer 1 (from step a) (0.23 g, 0.32 mmol) was dissolved inmethanol (10 ml) and a catalytic amount of 10% palladium on charcoal wasadded. The mixture was stirred under an atmosphere of hydrogenovernight, filtered and evaporated to leave the title compound (0.21 g,100%). The compound was characterised and tested as theN-methyl-D-glucamine salt, m.p. 130°-5°, α!^(D) =-18.5° (c=1 inmethanol), found: C, 67.17; H, 7.36; N, 6.49. C₄₇ H₅₈ N₄ O₉. H₂ Orequires C, 67.09; H, 7.19; N, 6.65%

EXAMPLE 56

Preparation of cis-7-2-R-(3-indolyl)-1-carboxy-ethylaminocarbonyl!-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereomer 2

The compound was prepared essentially as in example 4 but usingdiastereomer 2 (isolated in example 4 step a) instead of diastereomer 1in step b. Yield 90% The compound was further characterised and testedas the N-methyl-D-glucamine salt, m.p. 140°-5°, α!^(D) =-22.0° (c=1 inmethanol), found: C, 67.16; H, 7.18; N, 6.68. C₄₇ H₅₈ N₄ O₉. H₂ Orequires C, 67.09; H, 7.19; N, 6.65%

EXAMPLE 57

Preparation of cis-7-2-S-(3-indolyl)-1-carboxy-ethylaminocarbonyl!-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereomer 1

This was prepared essentially as in example 55 but using L-tryptophanbenzyl ester trifluoracetate instead of the D-isomer in step a.Separation of diastereomers was achieved at the benzyl ester stage asindicated in example 55 step a. and diastereomer 1 used in step b. wasagain the isomer with the higher R_(f). Overall yield 22% based onstarting racemic carboxylic acid.

The compound was further characterised and tested as theN-methyl-D-glucamine salt, m.p. 119°-24°, α!^(D) =-5.7° (c=0.7 inmethanol), found: C, 65.07; H, 7.25; N, 6.44. C₄₇ H₅₈ N₄ O₉ requires C,65.03; H, 7.32; N, 6.45%

EXAMPLE 58

Preparation of cis-7-2-S-(3-indolyl)-1-carboxy-ethylaminocarbonyl!-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereomer 2

The compound was prepared essentially as in example 55 but usingdiastereomer 2 (isolated in example 57 step a) instead of diastereomer 1in step b. Overall yield 26% based on starting racemic carboxylic acid.The compound was characterised and tested as the N-methyl-D-glucaminesalt, m.p. 133°-8°, α!^(D) =+7.6° (c=0.66 in methanol), found: C, 64.42;H, 7.17; N, 6.41. C₄₇ H₅₈ N₄ O₉. 3H₂ O requires C, 64.37; H, 7.35; N,6.39%

EXAMPLE 59

Preparation ofcis-(±)-7-(2-furanylmethylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo-2.2.2!octane

The reaction was performed essentially as in Example 25 but usingfurfurylamine instead of L-alanine methyl ester hydrochloride. Yield65%, m.p. 300°, found: C, 78.15; H, 6.99; N, 5.42. C₃₄ H₃₆ N₂ O₃requires C, 78.43; H, 6.97; N, 5.38%

EXAMPLE 60

Preparation of cis-(±)-7-2-(5-methyloxycarbonyl)-furanylaminocarbonyl!-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane

The reaction was performed essentially as in Example 25 but using5-methoxycarbonyl-2-aminofuran instead of L-alanine methyl esterhydrochloride. Yield 65%, m.p. 225°, found: C, 74.31; H. 6.54; N, 4.91.C₃₅ H₃₆ N₂ O₅ requires C, 74.45; H, 6.43; N, 4.96%

EXAMPLE 61

Preparation ofcis-7-(1-S-benzyloxycarbonyl-2-methylpropylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The reaction was performed essentially as in example 46 but using thep-toluenesulphonate salt of the benzyl ester of L-valine instead ofD-proline benzyl ester hydrochloride. m.p. 85°-87°. Found: C, 77.99; H,7.52; N, 4.17. C₄₁ H₄₆ N₂ O₄. 0.1H₂ O requires C, 77.86; H, 7.36; N,4.42%

EXAMPLE 62

Preparation ofcis-7-(1-S-carboxy-2-methyl-propylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo-2.2.2!octane (mixture of diastereomers)

The reaction was performed essentially as in example 48 but using theproduct of example 61 as substrate instead of the product of example 46.The compound was characterised and tested as the N-methyl-D-glucaminesalt m.p 105°-8°. Found: C, 64.00; H, 8.06; N, 5.37. C₄₁ H₅₇ N₃ O₉.1.8H₂ O requires C, 64.09; H, 7.95; N, 5.46%

EXAMPLE 63

Preparation ofcis-7-(1-S-methoxycarbonyl-2-methyl-propylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo-2.2.2!octane (mixture of diastereomers)

cis-7-(1-S-carboxy-2-methylpropylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo-2.2.2!octane (mixture of diastereomers) (150 mg) prepared as in example62 was dissolved in ethyl acetate (5 ml) and a solution of diazomethanein diethyl ether was added until a yellow colour persisted in solution.After stirring the reaction mixture at room temperature for 10 min,glacial acetic acid was added and the organic layer was washed withsaturated sodium hydrogencarbonate solution, dried over magnesiumsulphate, filtered and evaporated. Yield 130 mg, 85%, m.p. 103°-5°.Found: C, 75.51; H, 7.67; N, 5.06. C₃₅ H₄₂ N₂ O₄ requires C, 75.78; H,7.63; N, 5.05%

EXAMPLE 64

Preparation ofcis-7-(1-S-2-dicarboxyethyl-aminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

a.cis-7-(1-S-2-dibenzyloxycarbonylethylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo-2.2.2!octane (mixture of diastereomers)

The reaction was performed essentially as in example 46 but using thedibenzyl ester of L-aspartic acid instead of D-proline benzyl esterhydrochloride. The product was used directly in step b.

b.cis-7-(1-S-2-dicarboxyethylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo-2.2.2!octane (mixture of diastereomers)

The reaction was performed essentially as in example 48 but using theproduct of step a. as substrate instead of the product of example 46.The compound was characterised and tested as themono-N-methyl-D-glucamine salt, m.p 115°-7°. Found: C, 62.84; H, 7.03;N, 5.35. C₄₀ H₅₃ N₃ O₁₁. 0.62H₂ O requires C, 62.54; H, 7.03; N, 5.61%

EXAMPLE 65

Preparation of7-(1-S-carboxy-2-phenyl-ethyl-aminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The reaction was performed essentially as in example 64 but using thebenzyl ester of phenylalanine in step a. instead of the dibenzyl esterof aspartic acid. The compound was characterised and tested as theN-methyl-D-glucamine salt, m.p. 101°-3°. Found: C, 66.13; H, 7.64; N,5.05. C₄₅ H₅₇ N₃ O₉. 1.9H₂ O requires C, 66.06; H, 7.49; N, 5.14%

EXAMPLE 66

Preparation of(±)-cis-7-(1-methoxycarbonyl-1-methyl-ethylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane

The reaction was performed essentially as in example 46 but using thetrifluoromethylacetate salt of the methyl ester of aminoisobutyric acidinstead of D-proline benzyl ester hydrochloride. m.p 120°-2°. Found: C,75.51; H, 7.43; N, 4.90. C₃₄ H₄₀ N₂ O₄ requires C, 75.53; H, 7.46; N,5.18%

EXAMPLE 67

Preparation of(±)-cis-7-(1-carboxy-1-methyl-ethylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane

The reaction was performed essentially as in example 64 but using thebenzyl ester of aminoisobutyric acid in step a. instead of the dibenzylester of aspartic acid. The compound was characterised and tested as theN-methyl-D-glucamine salt, m.p 115°-25°. Found: C, 64.71; H, 7.74; N,5.92. C₄₀ H₅₅ N₃ O₉ requires C, 64.93; H, 7.76; N, 5.68%

EXAMPLE 68

Preparation ofcis-7-(2-R-carboxy-4-R-hydroxy-pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The reaction was performed essentially as in example 64 but using thebenzyl ester of cis hydroxy-D-proline in step a. instead of the dibenzylester of aspartic acid. The compound was characterised and tested as theN-methyl-D-glucamine salt, m.p 118°-21°. Found: C, 58.59; H, 7.48; N,5.10. C₄₁ H₅₅ N₃ O₁₀. 4.8 mol H₂ O requires C, 58.89; H, 7.78; N, 5.02%

EXAMPLE 69

Preparation ofcis-7-(2-R-carboxy-4R-hydroxypyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereomer 1

Thecis-7-(2-R-benzyloxycarbonyl-4-R-hydroxy-pyrrolidino-carbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane mixture of diastereomers prepared as referenced in example68 was separated into its two diastereomeric components by repeatedrecrystallisation from ethyl acetate. The insoluble isomer wasdesignated diastereomer 1. The soluble material isolated by evaporationwas designated diastereomer 2. Diastereomer 1 was converted to the titlecompound essentially as in example 48 using it as substrate instead ofthe product of example 46. The compound was characterised and tested asthe N-methyl-D-glucamine salt, m.p 112°-4°. Found: C, 60.81; H, 7.86; N,4.96. C₄₁ H₅₅ N₃ O₁₀. 4.4 mol H₂ O requires C, 60.70; H, 7.68; N, 5.18%

EXAMPLE 70

Preparation ofcis-7-(2-R-carboxy-4-R-hydroxypyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereomer 2

Diastereomer 2 prepared as described in example 69 was converted to thetitle compound essentially as in example 48 using it as substrateinstead of the product of example 46. The compound was characterised andtested as the N-methyl-D-glucamine salt, m.p. 132°-35°. Found: C, 63.69;H, 7.51; N, 5.04. C₄₁ H ₅₅ N₃ O₁₀. 1.5 mol H₂ O requires C, 63.40; H,7.52; N, 5.41%

EXAMPLE 71

Preparation ofcis-7-(2-R-methoxycarbonyl-4-R-hydroxypyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereomer 1

The compound was prepared essentially as in example 63 but using theproduct of example 69 as substrate instead ofcis-7-(1-S-carboxy-2-methylpropylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers), m.p 133°-35°. Found: C, 72.81;H, 7.21; N, 4.88. C₃₅ H₄₀ N₂ O₅. 0.5 mol H₂ O requires C, 72.81; H,7.15; N, 4.85% EXAMPLE 72

Preparation ofcis-7-(2-R-methoxycarbonyl-4-R-hydroxypyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2 !octane Diastereomer 2

The compound was prepared essentially as in example 63 but using theproduct of example 70 as substrate instead ofcis-7-(1-S-carboxyl)-2-methylpropylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers), m.p 133°-35°. Found: C, 70.28;H, 7.14; N, 4.81. C₃₅ H₄₀ N₂ O₅. 1.5 mol H₂ O requires C, 70.42; H,7.28; N, 4.69%

EXAMPLE 73

Preparation of(±)-cis-7-(3-(±)-carboxypiperidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane

The reaction was performed essentially as in example 46 but using thetrifluoromethylacetate salt of the benzyl ester of racemic nipecoticacid instead of D-proline benzyl ester hydrochloride. The compound wascharacterised and tested as the N-methyl-D-glucamine salt. Found: C,65.54; H, 8.12; N, 5.23. C₄₂ H₅₇ N₃ O₉. 1.4 H₂ O requires C, 65.24; H,7.80; N, 5.43%

EXAMPLE 74

Preparation of(±)-cis-7-(3-(±)-methoxycarbonylpiperidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane

The compound was prepared essentially as in example 63 but using theproduct of example 73 as substrate instead ofcis-7-(1-S-carboxy-2-methylpropylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers). Found: C, 74.24; H, 7.30; N,4.65. C₃₆ H₄₂ N₂ O₄. 0.8 H₂ O requires C, 74.40; H, 7.56; N, 4.82%

EXAMPLE 75

Preparation ofcis-7-(1-S-cyanoethylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of disastereomers)

The compound of example 31 (0.33 g, 0.59 mmol) was dissolved in pyridine(5 ml) and cooled to 0° under an atmosphere of dry argon. Tosyl chloride(0.13 g, 0.70 mmol) was added and the reaction allowed to warm to roomtemperature and was then stirred overnight. The solvent was removed byevaporation and the residue partitioned between ethyl acetate and water.The organic phase was washed successively with 1M hydrochloric acid andsaturated sodium hydrogen carbonate solution, dried, filtered andevaporated to leave the crude product. This material was purified bycolumn chromatography (silica, 90% dichloromethane and 10% ethylacetate) to leave the title compound (150 mg), m.p. 125°-8°. Found: C,76.30; H, 7.23; N, 8.21. C₃₂ H₃₅ N₃ O₂. 0.6 H₂ O requires C, 76.19; H,7.23; N, 8.32%

EXAMPLE 76

Preparation ofcis-7-(1-S-methylcarbonylethylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The compound of example 75 (0.25 g, 0.5 mmol) was dissolved in THF (3ml) and cooled to 0° under an atmosphere of dry argon. Methyl magnesiumbromide solution (1.4M in THF 1.4 ml, 2.0 mmol) was added. The solutionwas stirred at 0° for 1 h. 2M hydrochloric acid (2 ml ) was addedfollowed by saturated ammonium chloride solution. (20 ml). The productwas extracted with ethyl acetate (2×20 ml), dried, filtered andevaporated (0.25 ml). The crude product was purified by columnchromatography (silica 90% dichloromethane and 10% ethyl acetate) toleave the title compound (130 mg), m.p. 105°-10°. Found: C, 76.61; H,7.40; N, 5.25. C33H38N2O3. 0.4 H2O requires C, 76.54; H, 7.55; N, 5.41%

EXAMPLE 77

Preparation ofcis-7-(1-S-propyloxycarbonylethylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The reaction was performed essentially as in example 46 but using thetrifluoromethylacetate salt of the propyl ester of L-alanine (preparedfrom alklation of the caesium salt of BOC-L-alanine with propyl bromidefollowed by treatment with trifluoroacetic acid) instead of D-prolinebenzyl ester hydrochloride. m.p 90°-3°. Found: C, 75.33; H, 7.74; N,4.81. C₃₅ H₄₂ N₂ O₄. 0.25 H₂ O requires C, 75.33; H, 7.66; N, 5.01%

EXAMPLE 78

Preparation ofcis-7-(2-R-carboxy-pyrrolidinocarbonyl)8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereomer 1

The compound of example 48 was separated into its constituentdisastereomers by reverse phase HPLC (silica C8 column 60% acetonitrile,40% water and 0.1% acetic acid modifier). The first compound eluted wasdesignated diastereomer 1, the title compound. The compound wascharacterised and tested as the N-methyl-D-glucamine salt. Found: C,64.23; H, 7.86; N, 5.38. C₄₁ H₅₅ N₃ O₁₀. 1.8 H₂ O requires C, 64.22; H,7.71; N, 5.48%

EXAMPLE 79

Preparation ofcis-7-(2-R-carboxy-pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereomer 2

The second compound eluted during the HPLC separation referred to inexample 78 was designated diastereomer 2. The compound was characterisedand tested as the N-methyl-D-glucamine salt. Found: C, 64.23; H, 7.86;N, 5.38. C₄₁ H₅₅ N₃ O₁₀. 1.8 H₂ O requires C, 64.22; H, 7.71; N, 5.48%

EXAMPLE 80

Preparation ofcis-7-(2-S-methoxycarbonylpyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzocyclo2.2.2!octane Diastereomer 1

The compound of example 51 was separated into its constituentdiastereomers by repeated recrystallisation from 80% ethyl acetate and20% hexane. The crystals isolated were designated diastereomer 1, thetitle compound, m.p. 256°. Found: C, 76.07; H, 7.31; N, 4.98. C₃₅ H₄₀ N₂O₄ requires C, 76.06; H, 7.29; N, 5.07%

EXAMPLE 81

Preparation ofcis-7-(2-S-methoxycarbonylpyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereomer 2

The mother liquors from the recrystallisation described in example 80were concentrated to yield the other pure isomer designated diastereomer2, m.p. 94°-6°. Found: C, 74.88; H, 7.31; N, 5.03. C₃₅ H₄₀ N₂ O₄. 0.5 H₂O requires C, 74.91; H, 7.35; N, 4.99%

EXAMPLE 82

Preparation ofcis-7-(1-S-carboxy-2-hydroxyethylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereomer 1

Step a.cis-7-(1-S-Benzyloxycarbonyl-2-hydroxyethylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (diastereomer 1 and 2)

The reaction was performed essentially as in example 46 but usingL-serine benzyl ester hydrochloride instead of D-proline benzyl esterhydrochloride. The compound was separated into its componentdiastereomers by column chromatography (silica 25% ethyl acetate and 75%dichloromethane). The less polar material was designated diastereomer 1and the more polar diastereomer 2.

Step b.cis-7-(1-S-carboxy-2-hydroxyethylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2!octane Diastereomer 1

The reaction was performed essentially as in example 48 but using thediastereomer 1 from step a. above as substrate instead of the product ofexample 46. The compound was characterised and tested as theN-methyl-D-glucamine salt, m.p 102°-5° found: C, 61.24; H, 7.78; N,5.22. C₃₉ H₅₃ N₃ O₁₀. 2.4 H₂ O requires C, 61.08; H, 7.59; N, 5.48%

EXAMPLE 83

Preparation ofcis-7-(1-S-carboxy-2-hydroxyethylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereomer 2

The reaction was performed essentially as in example 48 but using thediastereomer 2 from example 82 step a. as substrate instead of theproduct of example 46. The compound was characterised and tested andtested as the N-methyl-D-glucamine salt, m.p 107°-10° found: C, 61.27;H, 7.69; N, 5.29. C₃₉ H₅₃ N₃ O₁₀. 2.3 H₂ O requires C, 61.19; H, 7.59;N, 5.49%

EXAMPLE 84

Preparation ofcis-7-(1-S-methoxycarbonyl-2-hydroxyethylaminocarbonyl)-8-(2,3,5,6-dibenzobicyclo2.2.2!octane Diastereomer 1

Step a.cis-7-(1-S-methoxycarbonyl-2-hydroxyethylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The reaction was performed essentially as in example 46 but usingL-serine methyl ester hydrochloride instead of D-proline benzyl esterhydrochloride.

Step b.cis-7-(1-S-methoxycarbonyl-2-hydroxyethylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereomer 1

The compound prepared in step a. was separated into its componentdiastereomers by column chromatography (silica 30% ethyl acetate and 70%dichloromethane). The less polar material was designated diastereomer 1,the title compound, m.p 115°-20° found: C, 68.94; H, 6.95; N, 4.91. C₃₃H₃₈ N₂ O₅. 1.6 H₂ O requires C, 69.26; H, 7.27; N, 4.90%

EXAMPLE 85

Preparation ofcis-7-(1-S-methoxycarbonyl-2-hydroxyethylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereomer 2

The compound of this example was the more polar diastereomer isolatedfrom the column chromatography described in example 84 step b, m.p100°-10° found: C, 56.92; H, 6.03; N, 3.49. C₃₃ H₃₈ N₂ O₅. 2.4 DCMrequires C, 56.91; H, 5.78; N, 3.75%

EXAMPLE 86

Preparation of (±)-cis-7-(1-methoxycarbonyl-1-ethyleneaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane

The product of example 64 step a. (270 mg, 0.5 mmol) was dissolved inTHF (2 ml) and N,N-carbonyldiimidazole (80 mg, 0.5 mmol) was addedfollowed by triethylamine (0.07 ml). The solution was stirred at roomtemperature overnight under an atmosphere of dry argon. The solvent wasevaporated and the crude material purified by column chromatography(silica 10% ethyl acetate and 90% dichloromethane) to give the titlecompound as a solid (50 mg), m.p 98°-108° found: C, 73.59; H, 7.05; N,5.06. C₃₃ H₃₆ N₂ O₄. 0.8 H₂ O requires C, 73.55; H, 7.03; N, 5.20%

EXAMPLE 87

Preparation ofcis-7-(1-S-methoxycarbonyl-2-carboxyethylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The reaction was performed essentially as in example 64 but using thealpha methyl beta benzyl diester of aspartic acid in step a. instead ofthe dibenzyl ester. The compound was characterised and tested as theN-methyl-D-glucamine salt, m.p 103°-5° found: C, 56.56; H, 7.70; N,4.71. C₄₁ H₅₅ N₃ O₁₁. 5.9 H₂ O requires C, 56.48; H, 7.72; N, 4.82%

EXAMPLE 88

Preparation ofcis-7-(2-R-carboxypiperidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The reaction was performed essentially as in example 64 but using thebenzyl ester of D-pipecolinic acid in step a. instead of the dibenzylester of aspartic acid. The compound was characterised and tested as theN-methyl-D-glucamine salt. Found: C, 65.13; H, 8.07; N, 5.64. C₄₂ H₅₇ N₃O₉. 1.5 H₂ O requires C, 65.10; H, 7.81; N, 5.42%

EXAMPLE 89

Preparation ofcis-7-(2-R-methoxycarbonylpiperidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The compound was prepared essentially as in example 63 but using theproduct of example 88 as substrate instead ofcis-7-(1-S-carboxy-2-methylpropylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers). Found: C, 70.00; H, 7.18; N,4.70. C₃₆ H₄₂ N₂ O₄. 0.5 CHCl₃ requires C, 70.04; H, 6.78; N, 4.40%

EXAMPLE 90

Preparation ofcis-7-(2-S-methoxycarbonyl-4-S-hydroxypyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The reaction was performed essentially as in example 46 but using thetrifluoroacetate salt of the methyl ester of cis-hydroxy-L-prolineinstead of D-proline benzyl ester hydrochloride. Found: C, 76.36; H,7.24; N, 4.38. C₃₅ H₄₀ N₂ O₅. 0.9 toluene requires C, 76.25; H, 7.31; N,4.26%

EXAMPLE 91

Preparation ofcis-7-(2-S-methoxycarbonyl-4-R-hydroxypyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The reaction was performed essentially as in example 46 but using thetrifluoroacetate salt of the methyl ester of trans-hydroxy-L-prolineinstead of D-proline benzyl ester hydrochloride. Found: C, 75.16; H,7.32; N, 4.19. C₃₅ H₄₀ N₂ O₅. 0.6 toluene requires C, 75.45; H, 7.24; N,4.49%

EXAMPLE 92

Preparation ofcis-7-(1-S-methoxycarbonyl-2-benzylsulphenylethylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereomer 1

Step a.cis-7-(1-S-methoxycarbonyl-2-benzylsulphenylethylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The reaction was performed essentially as in example 46 but using thebenzylthioether of L-cysteine methyl ester hydrochloride instead ofD-proline benzyl ester hydrochloride.

Step b.cis-7-(1-S-methoxycarbonyl-2-benzylsulphenylethylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereomer 1

The compound prepared in step a. was separated into its componentdiastereomers by column chromatography (silica 15% ethyl acetate and 85%dichloromethane). The more polar material (R_(f) 0.4) was designateddiastereomer 1, the title compound, m.p. 80°-1° found: C, 72.93; H,6.88; N, 4.08. C₄₀ H₄₄ N₂ O₄ S. 0.5 H₂ O requires C, 73.04; H, 6.89; N,4.25%

EXAMPLE 93

Preparation ofcis-7-(1-S-methoxycarbonyl-2-benzylsulphenylethylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereomer 2

The less polar material isolated by the chromatography (R_(f) 0.6)described in example 92 step b. was designated as diastereomer 2, m.p.85° found: C, 74.03; H, 7.01; N, 4.38. C₄₀ H₄₄ N₂ O₄ S requires C,74.04; H, 6.64; N, 4.32%

EXAMPLE 94

Preparation ofcis-7-(1-S-carboxyethyl-(N-methyl)aminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The reaction was performed essentially as in example 64 but using thetrifluoroacetate salt of the benzyl ester of N-methyl-L-alanine in stepa. instead of the dibenzyl ester of aspartic acid. The compound wascharacterised and tested as the N-methyl-D-glucamine salt, m.p. 100°-10°found: C, 64.12; H, 7.89; N, 5.71. C₄₀ H₄₅ N₃ O₉. 1.5 H₂ O requires C,64.21; H, 7.80; N, 5.62%

EXAMPLE 95

Preparation ofcis-7-(1-R-carboxyethyl-(N-methyl)-aminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The reaction was performed essentially as in example 64 but using thetrifluoroacetate salt of the benzyl ester of N-methyl-D-alanine in stepa. instead of the dibenzyl ester of aspartic acid. The compound wascharacterised and tested as the N-methyl-D-glucamine salt, m.p. 105°-15°found: C, 62.06; H, 7.81; N, 5.55. C₄₀ H₅₅ N₃ O₉. 2.8 H₂ O requires C,62.18; H, 7.91; N, 5.44%

EXAMPLE 96

Preparation ofcis-7-(1-S-methoxycarbonylethyl-(N-methyl)-aminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The reaction was performed essentially as in example 63 but using theproduct of example 94 as substrate instead ofcis-7-(1-S-carboxy-2-methylpropylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers), m.p. 96°-8° found: C, 75.55; H,7.68; N, 5.10. C₃₄ H₄₀ N₂ O₄ requires C, 75.53; H, 7.46; N, 5.18%

EXAMPLE 97

Preparation ofcis-7-(1-R-methoxycarbonylethyl-(N-methyl)-aminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The reaction was performed essentially as in example 63 but using theproduct of example 95 as substrate instead ofcis-7-(1-S-carboxy-2-methlpropylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers), m.p. 95°-105° found: C, 75.49;H, 7.53; N, 5.24. C₃₄ H₄₀ N₂ O₄ requires C, 75.53; H, 7.46; N, 5.18%

EXAMPLE 98

Preparation of(±)-cis-7-(pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane

The reaction was performed essentially as in example 64 but usingpyrrolidine in step a. instead of the dibenzyl ester of aspartic acid,m.p. 205°-7° found: C, 80.15; H, 7.77; N, 5.78. C₃₃ H₃₈ N₂ O₂ requiresC, 80.12; H, 7.74; N, 5.66%

EXAMPLE 99

Preparation of(±)-cis-7-(methylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane

The compound of example 14 (440 mg, 1 mmol) was dissolved indichloromethane (15 ml) and diisopropylethylamine (0.52 ml) and PyBOP(520 mg) were added. The solution was stirred for 5-10 min until a clearsolution was obtained. Dry methylamine gas was bubbled through thesolution for 5 min until this was saturated. The solution was stirredfor 1 h and then evaporated. The residue was taken up in ethyl acetateand washed successively with 5% aqueous potassium hydrogensulphatesolution (2×20 ml) saturated sodium hydrogencarbonate solution (20 ml),brine (20 ml), dried, filtered and evaporated to leave a crude productwhich was purified by column chromatography (silica 70% dichloromethaneand 30% ethyl acetate). The title compound was a white solid (240 mg),m.p. 192°-3° found: C, 79.15; H, 7.72; N, 5.91. C₃₀ H₃₄ N₂ O₂ requiresC, 79.26; H, 7.53; N, 6.16%

EXAMPLE 100

Preparation of(±)-cis-7-(dimethylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane

The compound was prepared essentially as in example 99 but usingdimethylamine instead of methylamine, m.p. 253°-5° found: C, 78.86; H,7.78; N, 5.67. C₃₁ H₃₆ N₂ O₂ requires C, 78.69; H, 7.8 N, 5.92%

EXAMPLE 101

Preparation of(±)-cis-7-(ethylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane

The compound was prepared essentially as in example 99 but usingethylamine instead of methylamine, m.p. 200°-1° found: C, 79.82; H,7.67; N, 5.94. C₃₁ H₃₆ N₂ O₂ requires C, 79.45; H, 7.74 N, 5.98%

EXAMPLE 102

Preparation of(±)-cis-7-(1-methylethylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane

The compound was prepared essentially as in example 99 but usingisopropylamine instead of methylamine, m.p. 122°-4° found: C, 74.80; H,7.21; N, 5.38. C₃₂ H₃₈ N₂ O₂. 0.4 DCM. 0.1 ethyl acetate requires C,74.94; H, 7.56 N, 5.33%

EXAMPLE 103

Preparation of(±)-cis-7-aminocarbonyl-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane

The compound was prepared essentially as in example 99 but using ammoniainstead of methylamine, m.p. 238°-40° found: C, 78.78; H, 7.45; N, 6.41.C₂₉ H₃₂ N₂ O₂ requires C, 79.06; H, 7.32 N, 6.36%

EXAMPLE 104

Preparation of(±)-cis-7-(2-benzyloxycarbonylethylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-1-cyano-2,3,5,6-dibenzobicyclo2.2.2!octane Regioisomer 1

The mixture of regioisomers was prepared essentially as in example 29but using(±)-cis-8-(1-adamantylmethylaminocarbonyl)-1-cyano-2,3,5,6-dibenzobicyclo2.2.2!octane-7-carboxylic acid instead of(±)-cis-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane-7-carboxylic acid. This in turn was made by reaction of1-adamantanemethylamine with 1-cyano-2,3,5,6-dibenzobicyclo2.2.2!octane-7,8-dicarboxylic acid anhydride essentially as in example14. The anhydride was prepared by reaction of maleic anhydride with9-cyanoanthracene in refluxing toluene. The regioisomers were separatedby preparative HPLC (silica, ethyl acetate 15% and dichloromethane 85%).The less polar regioisomer was designated regioisomer 1, the titlecompound, m.p. 205°-8° found: C, 76.55; H, 6.61; N, 6.68. C₄₀ H₄₁ N₃ O₄requires C, 76.53; H, 6.58; N, 6.69%

EXAMPLE 105

Preparation of(±)-cis-7-(2-benzyloxycarbonylethylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-1-cyano-2,3,5,6-dibenzobicyclo2.2.2!octane Regioisomer 2

The more polar regioisomer from the HPLC separation described in example104 was designated regioisomer 2, the title compound, m.p. 104°-7°found: C, 76.48; H, 6.65; N, 6.59. C₄₀ H₄₁ N₃ O₄ requires C, 76.53; H,6.58; N, 6.69%

EXAMPLE 106

Preparation ofcis-7-(1-S-methoxycarbonylethylaminocarbonyl)-8-(neopentylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

a. (±)-8-(neopentylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane-7-carboxylic acid

The material was prepared essentially as in example 14 but usingneopentylamine hydrochloride as substrate instead of 1-adamantylamine.

b.cis-7-(1-S-methoxycarbonylethylaminocarbonyl)-8-(neopentylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The material was prepared essentially as in example 25 but using thecompound prepared in step a. above instead of(±)-cis-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane-7-carboxylic acid as substrate. found: C, 72.14; H, 7.32;N, 6.29. C₂₇ H₃₂ N₂ O₄ requires C, 72.30; H, 7.19; N, 6.25%

EXAMPLE 107

Preparation ofcis-7-(2-R-carboxy-pyrrolidinocarbonyl)-8-(neopentylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

a.cis-7-(2-R-benzyloxycarbonylpyrrolidinocarbonyl)-8-(neopentylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers). The compound was preparedessentially as in example 46 but using the product of example 106 stepa. as substrate instead of(±)-cis-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane-7-carboxylic acid.

b.cis-7-(2-R-carboxypyrrolidinocarbonyl)-8-(neopentylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The reaction was performed essentially as in example 48 but using theproduct of example 107 step a. as substrate instead of the product ofexample 46. The compound was characterised and tested as theN-methyl-D-glucamine salt, m.p. 105°-15° found: C, 57.98; H, 7.89; N,6.07. C₃₅ H₄₉ N₃ O₉. 4.0 H₂ O requires C, 57.75; H, 7.89; N, 5.77%

EXAMPLE 108

Preparation of 7-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!oct-7,8-ene

a. 7-carboxy-2,3,5,6-dibenzobicyclo 2.2.2!oct-7,8-ene

7-(methoxycarbonyl)-2,3,5,6-dibenzobicyclo 2.2.2!oct-7,8-ene (preparedas in J.C.S. Perkin I, 1984, 779) (0.5 g, 1.9 mmol) was dissolved inethanol (20 ml) and sodium hydroxide (0.5 g) was added along with water(2 ml). The solution was stirred and refluxed for 1.5 h. The hotsolution was poured onto 2M HCl (50 ml). The white precipitate formedwas filtered off, washed with water and dried at 50° in vacuo. Thiscompound was used without further purification.

b. 7-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!oct-7,8-ene

The acid prepared in step a. above (248 mg, 1 mmol) was dissolved in drydichloromethane (10 ml) and diisopropylamine (0.52 g, 3 mmol) and PyBOP(0.52 g, 1 mmol) were added. After stirring at room temperature for 5min, 1-adamantylmethylamine (180 mg) was added. After stirring for afurther 30 min whereupon the reaction mixture was evaporated. Theresidue was taken up in ethyl acetate and washed successively with 5%aqueous potassium hydrogensulphate solution (2×20 ml), saturated sodiumhydrogencarbonate solution (20 ml), brine (20 ml), dried, filtered andevaporated to leave a crude product which was recrystallised fromtoluene. The white solid was dried in vacuo, m.p. 254°-5° found: C,81.28; H, 7.81; N, 3.40. C₂₈ H₂₉ NO. H₂ O requires C, 81.32; H, 7.50; N,3.39%

EXAMPLE 109

Preparation of(±)-7-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane

a. (±)-2,3,5,6-dibenzobicyclo 2.2.2!octane-7-carboxylic acid

7-(methoxycarbonyl)-2,3,5,6-dibenzobicyclo 2.2.2!octane (prepared as inU.S. Pat. No. 5,055,468) (20 g, 80 mmol) was dissolved in methanol (220ml) and potassium hydroxide (40 g) was added along with water (40 ml).The solution was stirred and refluxed for 4 h. The solution was cooled,filtered through charcoal and treated with concentrated HCl. The buffprecipitate formed was filtered off, washed with water andrecrystallised from hot benzene. This compound was used without furtherpurification.

b. (±)-7-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane

(±)-2,3,5,6-dibenzobicyclo 2.2.2!octane-7-carboxylic acid (prepared instep a. above) (1.0 g) was heated with thionyl chloride (5 ml) and DMF(2 drops) at reflux for 30 min. On cooling and evaporation the paleyellow acid chloride was isolated.

The acid chloride (267 mg, 1.0 mmol) was dissolved in drydichloromethane (5 ml) and added with stirring to a solution of1-adamantanemethylamine (182 mg, 1.1 mmol) and triethylamine (0.3 ml).After 30 min the solution was washed successively with 2M HCl and brine,dried, filtered and evaporated to leave a solid which was recrystallisedfrom toluene (253 mg), m.p. 220°-1° found: C, 84.88; H, 7.81; N, 3.39.C₂₈ H₃₁ NO requires C, 84.81; H, 7.63; N, 3.39%

EXAMPLE 110

Preparation of (±)-7-(1-adamantylmethoxycarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane

The material was prepared essentially as in example 109 except that1-adamantanemethanol was used instead of 1-adamantanemethylamine in stepb, m.p. 152°-3° found: C, 84.42; H, 7.65. C₂₈ H₃₀ O₂ requires C, 84.38;H, 7.59%

EXAMPLE 111

Preparation ofcis-7-(1-S-methoxycarbonylethylaminocarbonyl)-8-(1-adamantylmethoxycarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The material was prepared essentially as in example 25 but using thecompound prepared in example 13 instead of(±)-cis-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane-7-carboxylic acid as substrate, m.p. 75°-7° found: C,74.27; H, 7.36; N, 2.80. C₃₃ H₃₇ NO₅. 0.06 mol DCM requires C, 74.53; H,7.02; N, 2.62%

EXAMPLE 112

Preparation ofcis-7-(1-R-methoxycarbonylethyl-aminocarbonyl)-8-(1-adamantylmethoxycarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The material was prepared essentially as in example 111 but usingD-alanine methyl ester hydrochloride instead of L-alanine methyl esterhydrochloride as substrate, m.p. 85°-7° found: C, 74.38; H, 7.29; N,2.75. C₃₃ H₃₇ NO₅. 0.05 mol DCM requires C, 74.63; H, 7.03; N, 2.63%

EXAMPLE 113

Preparation of(±)-cis-7-(2-benzyloxycarbonylethyl-aminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-1,4-dimethyl-2,3,5,6-dibenzobicyclo2.2.2!octane

The compound was prepared essentially as in example 29 but using(±)-cis-8-(1-adamantylmethylaminocarbonyl)-1,4-dimethyl-2,3,5,6-dibenzobicyclo2.2.2!octane-7-carboxylic acid instead of(±)-cis-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo-2.2.2!octane-7-carboxylic acid. This in turn was made by reaction of1-adamantanemethylamine with 1,4-dimethyl-2,3,5,6-dibenzobicyclo2.2.2!octane-7,8-dicarboxylic acid anhydride essentially as in example14. The anhydride was prepared by reaction of maleic anhydride with9,10-dimethylanthracene in refluxing toluene. m.p. 170°-3° found: C,77.89; H, 7.49; N, 4.49. C₄₁ H₄₆ N₂ O₄ requires C, 78.06; H, 7.49; N,4.44%

EXAMPLE 114

Preparation of(±)-cis-7-(1-S-methoxycarbonylethyl-aminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-1-nitro-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereomer 1

The compound was prepared essentially as in example 25 but using(±)-cis-8-(1-adamantylmethylaminocarbonyl)-1-nitro-2,3,5,6-dibenzobicyclo2.2.2!octane-7-carboxylic acid instead of(±)-cis-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzo-bicyclo2.2.2!octane-7-carboxylic acid. This in turn was made by reaction of1-adamantanemethylamine with 1-nitro-2,3,5,6-dibenzobicyclo-2.2.2!octane-7,8-dicarboxylic acid anhydride essentially as in example14. The anhydride was prepared by reaction of maleic anhydride with9-nitroanthracene in refluxing toluene. The final mixture ofdiastereomers was separated into three components by HPLC (silicagradient elution of 5% ethyl acetate and 95% dichloromethane to 15%ethyl acetate and 85% dichloromethane). The least polar fraction wasdesignated diastereomer 1. Found: C, 68.99; H, 6.78; N, 7.24. C₃₃ H₃₇ N₃O ₆ requires C, 69.33; H, 6.52; N, 7.35%

EXAMPLE 115

Preparation of(±)-cis-7-(1-S-methoxycarbonylethyl-aminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-1-nitro-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereomer 2

The second least polar fraction from the HPLC separation described inexample 114 was designated diastereomer 2. Found: C, 69.43; H, 6.69; N,7.37. C₃₃ H₃₇ N₃ O₆ requires C, 69.33; H, 6.52; N, 7.35%

EXAMPLE 116

Preparation of(±)-cis-7-(1-S-methoxycarbonylethyl-aminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-1-nitro-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereomer 3

The most polar fraction from the HPLC separation described in example114 was designated diastereomer 3, found: C, 69.21; H, 6.80; N, 7.22.C₃₃ H₃₇ N₃ O₆ requires C, 69.33; H, 6.52; N, 7.35%

EXAMPLE 117

Preparation ofcis-7-(1-S-methoxycarbonyl-2-(3-indolyl)ethylaminocarbonyl)-8-(neopentylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The compound was prepared essentially as in example 54 but using theproduct of example 106 step a. as substrate instead of(±)-cis-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane-7-carboxylic acid. Found: C, 73.81; H, 6.49; N, 7.23. C₃₅H₃₇ N₃ O₄. 0.25 H₂ O requires C, 73.98; H, 6.65; N,

EXAMPLE 118

Preparation ofcis-7-(1-S-carboxy-2-(3-indolyl)ethylaminocarbonyl)-8-(neopentylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The compound was prepared essentially as in example 107 but using thebenzyl ester of L-tryptophan as substrate in step a. as substrateinstead of the benzyl ester of D-proline. The compound was characterisedand tested as the N-methyl-D-glucamine salt Found: C, 65.91; H, 7.01; N,7.31. C₄₁ H₅₂ N₄ O₉ requires C, 66.11; H, 7.04; N, 7.52%,

EXAMPLE 119

Preparation of cis-7-(2-R-(carboxymethylamino-carbonyl)pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The reaction was performed essentially as in example 64 but using thebenzyl ester of D-prolylglycine in step a. instead of the dibenzyl esterof aspartic acid. The compound was characterised and tested as theN-methyl-D-glucamine salt. Found: C, 61.52; H, 7.52; N, 6.81. C₄₃ H₅₈ N₄O₁₀. 2.6 H₂ O requires C, 61.65; H, 7.60; N, 6.69%

EXAMPLE 120

Preparation ofcis-7-(2-R-(carboxymethylamino-carbonyl)pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereomer 1

The benzyl ester intermediate isolated after example 119 step a. wasseparated into its constituent diastereomers by recrystallisation fromethyl acetate. The mother liquors on concentration gave a benzyl esterwhich on hydrogenolysis gave the diastereomer of this example. Thecompound was characterised and tested as the N-methyl-D-glucamine salt.Found: C, 65.12; H, 7.40; N, 6.95. C₄₃ H₅₈ N₄ O₁₀ requires C, 65.30; H,7.39; N, 7.08%

EXAMPLE 121

Preparation of cis-7-(2-R-(carboxymethylamino-carbonyl)pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereomer 2

The crystalline material from the recrystallisation described in example120 on hydrogenolysis gave the diastereomer of this example. Thecompound was characterised and tested as the N-methyl-D-glucamine salt.Found: C, 61.54; H, 7.75; N, 6.34. C₄₃ H₅₈ N₄ O₁₀. 2.9 H₂ O requires C,61.29; H, 7.62; N, 6.64%

EXAMPLE 122

Preparation of cis-7-(2-R-(carboxyethylamino-carbonyl)pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The reaction was performed essentially as in example 64 but using thebenzyl ester of D-prolyl-beta-alanine in step a. instead of the dibenzylester of aspartic acid. The compound was characterised and tested as theN-methyl-D-glucamine salt. Found: C, 63.14; H, 7.78; N, 6.60. C₄₄ H₆₀ N₄O₁₀. 1.9 H₂ O requires C, 63.02; H, 7.66; N, 6.68%

EXAMPLE 123

Preparation ofcis-7-(2-(methoxycarbonylmethylaminocarbonyl)pyrrolidinocarbonyl)-8-(1-adamantylmethylamino-carbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The compound was prepared essentially as in example 63 but using thecompound of example 119 as substrate instead of the compound of example62. Found: C, 69.77; H, 7.08; N, 6.58. C₃₇ H₄₃ N₃ O₅. 1.4 H₂ O requiresC, 69.97; H, 7.27; N, 6.62%

EXAMPLE 124

Preparation ofcis-7-(2-R-(methoxycarbonylethylaminocarbonyl)pyrrolidinocarbonyl)-8-(1-adamantylmethylamino-carbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The compound was prepared essentially as in example 63 but using thecompound of example 122 as substrate instead of the compound of example62. Found: C, 71.15; H, 7.40; N, 6.56. C₃₈ H₄₅ N₃ O₅. H₂ O requires C,71.13; H, 7.38; N, 6.54%

EXAMPLE 125

Preparation ofcis-7-(1-S-(carboxyethylamino-carbonyl)ethylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The reaction was performed essentially as in example 64 but using thebenzyl ester of L-alanyl-beta-alanine in step a. instead of the dibenzylester of aspartic acid. The compound was characterised and tested as theN-methyl-D-glucamine salt. Found: C, 60.56; H, 7.74; N, 6.53. C₄₂ H₅₈ N₄O₁₀. 3.1 H₂ O requires C, 60.40; H, 7.75; N, 6.71%

EXAMPLE 126

Preparation ofcis-7-(1-S-(methoxycarbonylethylaminocarbonyl)ethylaminocarbonyl)-8-(1-adamantylmethylamino-carbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The compound was prepared essentially as in example 63 but using thecompound of example 125 as substrate instead of the compound of example62. Found: C, 69.51; H, 7.39; N, 6.49. C₃₆ H₄₃ N₃ O₅. 1.4 H₂ O requiresC, 69.35; H, 7.41; N, 6.73%

EXAMPLE 127

Preparation ofcis-7-(1-S-(methylaminocarbonyl)ethylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The compound was prepared essentially as in example 25 but using thetrifluoroacetate salt of N-methyl-L-alaninamide instead of L-alaninemethyl ester hydrochloride. Found: C, 72.12; H, 7.37; N, 7.50. C₃₃ H₃₉N₃ O₃. 1.2 H₂ O requires C, 72.37; H, 7.63; N, 7.67%

EXAMPLE 128

Preparation ofcis-7-(1-S-(methoxycarbonyl)-ethylaminocarbonyl)-8-(1-RS-(1-adamantyl)ethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers A)

a. 8-(1-(1-adamantyl)ethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane-7-carboxylic acid (mixture of diastereomers)

This compound was prepared essentially as in example 14 but using1-RS-(1-adamantyl)ethylamine (prepared as described in EP 178668) assubstrate instead of 1-adamantanemethylamine.

b.cis-7-(1-S-(methoxycarbonyl)ethylaminocarbonyl-8-(1-RS-(1-adamantyl)ethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers A)

This was prepared essentially as in example 25 but using the product ofstep a. instead of the product of example 14. The mixture of fourcompounds thus produced was separated into two pairs by use ofpreparative MPLC (silica 35% ethyl acetate and 65% hexane). The leastpolar pair were designated as the product of this example. found: C,74.26; H, 7.60; N, 4.86. C₃₄ H₄₀ N₂ O₄. 0.5 H₂ O requires C, 74.29; H,7.52; N, 5.10%

EXAMPLE 129

Preparation ofcis-7-(1-S-(methoxycarbonyl)ethylaminocarbonyl)-8-(1-RS-(1-adamantyl)ethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers B)

The most polar pair of compounds isolated after the MPLC proceduredescribed in example 128 were designated mixture B, the compounds ofthis example, Found: C, 74.01; H, 7.69; N, 4.90. C₃₄ H₄₀ N₂ O₄. 0.5 H₂ Orequires C, 74.29; H, 7.52; N, 5.10%

EXAMPLE 130

Preparation ofcis-7-(1-S-(ethylcarbonyl)ethylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The compound of example 75 (0.37 g, 0.74 mmol) was dissolved in THFunder an atmosphere of argon and cooled to 0°. A 1M solution of ethylmagnesium bromide in THF (3 ml) was added and the solution stirred for afurther 2 h before being allowed to warm to room temperature forovernight stirring. The reaction was quenched with 2M hydrochloric acidand after evaporation the product was dissolved in ethyl acetate andwashed successively with saturated aqueous sodium hydrogencarbonate andwith brine. The organic layer was dried, filtered and evaporated toleave the crude product which was purified by column chromatography(silica 90% dichloromethane and 10% ethyl acetate). Yield 0.19 g, 50%,m.p 105°-8°. Found: C, 77.87; H, 7.61; N, 5.22. C₃₄ H₄₀ N₂ O₃ requiresC, 77.83; H, 7.68; N, 5.34%

EXAMPLE 131

Preparation of(±)-7-(methoxycarbonylmethyl)-cis-7-carboxy-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane

a. Diels-Alder adduct of the methyl ester of aconitic anhydride andanthracene

The methyl ester of aconitic anhydride (10.2 g, 60 mmol) was dissolvedin dry dichloromenthane (200 ml) and anthracene (7.12 g, 40 mmol) wasadded followed by anhydrous aluminium chloride (9.0 g, 60 mmol). Thesolution was stirred at room temperature overnight and then poured ontoa mixture of ice and hydrochloric acid. The organic layer was separatedand dried, filtered and evaporated to leave an orange oil which wasrecrystallised from toluene after treatment with activated charcoal. Theproduct, a buff solid, was dried in air (9.01 g) and used in the nextstep.

b.(±)-7-(methoxycarbonylmethyl)-cis-7-carboxy-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane

The material was prepared essentially as in example 14 but using thematerial prepared in step a. above instead of (±)-2,3,5,6-dibenzobicyclo2.2.2!octane-7,8-dicarboxylic anhydride. The compound was characterisedand tested as the N-methyl-D-glucamine salt found: C, 65.72; H, 7.61; N,3.83. C₃₉ H₅₂ N₂ O₁₀ requires C, 66.08; H, 7.39; N, 3.95%

EXAMPLE 132

Preparation ofcis-7-(1-S-methoxycarbonyl)ethylaminocarbonyl)-8-(2-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The compound was prepared essentially as in example 25 but using thecompound of example 39 instead of8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane-7-carboxylic acid as substrate, m.p. 105°-110°. Found C,74.13; H, 7.17; N, 4.85. C₃₃ H₃₈ N₂ O₄.0.5 H₂ O requires C, 73.99; H,7.33; N, 5.23%

EXAMPLE 133

Preparation ofcis-7-(2-R-carboxypyrrolidinocarbonyl)8-(2-adamantylmethylamethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The benzyl ester of the compound was prepared essentially as in example46 but using the compound of example 39 instead of8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane-7-carboxylic acid as substrate. The hydrogenolysis wasperformed as described in example 48. m.p. 105°-110°. The compound wasfurther characterised and tested as its N-methyl-D-glucamine salt found:C, 64.86; H, 7.79; N, 5.19. C₄₁ H₅₅ N₃ O₉. 1.6H₂ O requires C, 64.56; H,7.69; N, 5.51%

EXAMPLE 134

Preparation of 8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!oct-7-ene-7-carboxylic acid

a. dimethyl-2,3,5,6-dibenzobicyclo 2.2.2!oct-7-ene-7,8-dicarboxylate

The Diels-Alder reaction between anthracene (10 g, 0.06 mol) anddimethyl acetylenedicarboxylate (8.3 ml, 0.07 mol) was performedessentially as in step a. of example 1 with the exeption that thereactants were refluxed for 24 hours.

b. 2,3,5,6,-dibenzobicyclo 2.2.2!oct-7-ene-7,8-dicarboxylic acid

To a solution of potassium hydroxide (1.05 g, 18.8 mmol) in water (30ml) was added the solution of the product of step a. (2.0 g, 6.2 mmol)in dioxan (10 ml). The reaction mixture was heated to reflux for 20mins, cooled to room temperature and diluted with 2N hydrochloric acid.The precipitated solid was filtered, washed with water and dried (1.42 g78%).

c. 2,3,5,6,-dibenzobicyclo 2.2.2!oct-7-ene-7,8-dicarboxylic acidanhydride

A mixture of the product of step b (1.4 g, 4.8 mmol and acetic anhydride(36 ml) was heated at reflux for 45 mins. The solvent was evaporated andthe residue was triturated with diethyl ether to afford white solid(0.73 g, 55%).

d. 8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!oct-7-ene-7-carboxylic acid

This was performed essentially as in example 14 using the product ofstep c above as substrate instead of 2,3,5,6-dibenzobicylo2.2.2!oct-7,8-dicarboxylic anhydride. The compound was characterised andtested as the N-methyl-D-glucamine salt. Found: C, 67.79; H, 7.51; N,4.33. C₃₆ H₄₆ N₂ O₈ requires C, 68.12; H, 7.30; N, 4.41%

EXAMPLE 135

Preparation ofcis-7-(1-S-methoxycarbonyl-ethylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!oct-7-ene

This was performed essentially as in example 25 using the product ofexample 134 as substrate instead of(±)-cis-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!oct-7-carboxylic acid found: C, 75.45; H, 6.79; N, 5.26. C₃₃ H₃₆N₂ O₄ requires C, 75.55; H, 6.92; N, 5.34%

EXAMPLE 136

Preparation ofcis-7-(2-R-(carboxymethylaminocarbonyl)pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl-2,3,5,6-dibenzobicyclo2.2.2!oct-7-ene

This was performed essentially as in example 119 using the product ofexample 134 as substrate instead of8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!oct-7-carboxylic acid. The compound was tested as theN-methyl-D-glucamine salt.

EXAMPLE 137

Preparation ofcis-7-(2-R-carboxy-pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-1,4-difluro-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

a. Diels alder reaction

This was performed essentially as in step a. of example 1 using9,10-difluoroanthracene (prepared as in J.Org.Chem., 1989, 54, 1018) assubstrate instead of anthracene.

b.(±)-cis-8-(1-adamantylmethylaminocarbonyl)-1,4-difluro-2,3,5,6-dibenzobicyclo2.2.2!octane-7-carboxylic anhydride.

This was performed essentially as in example 14 using the product ofstep a. above as substrate instead of 2,3,5,6-dibenzobicyclo2.2.2!oct-7,8-dicarboxylic anhydride

c. cis-7-(2-R-benzyloxycarbonylprrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-1,4-difluoro-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

This was performed essentially as in example 46 using the product ofstep b above as substrate instead of(±)-cis-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!oct-7-carboxylic acid

d.cis-7-(2-R-carboxy-pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-1,4-difluoro-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

This was performed essentially as in example 48 using the product of thestep c above as substrate instead of the product of example 46. Thecompound was characterised and tested as the N-methyl-D-glucamine salt.Found: C, 57.48; H, 7.43; N, 528. C₄₁ H₅₃ F₂ N₃ O₉. 4.5 H₂ O requires C,57.82; H, 7.35; N, 4.93%

Example 138

Preparation ofcis-7-(2-R-carboxy-4-R-hydroxypyrrolidinocarbonyl)-8-(2-adamantylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

a. (±)-cis-8-(2-adamantylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane-7-carboxylic acid

This was prepared essentially as in example 11 using 2-adamantamine assubstrate instead of 1-adamantamine.

b.cis-7-(2-R-benzyloxycarbonyl-4-R-hydroxy-pyrrolidinocarbonyl)-8-(2-adamantylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

This was performed essentially as in example 46 using the product ofstep a. above as substrate instead ofcis-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!oct-7-carboxylic acid

c.7-(2-R-carboxy-4-R-hydroxy-pyrrolidinocarbonyl)-8-(2-adamantylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

This was performed essentially as in example 48 using the product ofstep b above as substrate instead of the product of example 46. Thecompound was characterised and tested as the N-methyl-D-glucamine salt.Found: C, 60.86; H, 7.40; N, 5.31. C₄₀ H₅₃ N₃ O₁₀. 2.9H₂ O requires C,60.97; H, 7.52; N, 5.33%

EXAMPLE 139

Preparation ofcis-7-(2-S-carboxypiperidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The reaction was performed essentially as in example 64 but using thebenzyl ester of L-pipecolinic acid in step a. instead of the dibenzylester of aspartic acid. The compound was further characterised andtested as the N-methyl-D-glucamine salt. Found: C, 64.39; H, 7.97; N,5.28. C₄₂ H₅₇ N₃ O₉. 2.0H₂ O requires C, 64.35; H, 7.84; N, 5.36%

EXAMPLE 140

Preparation ofcis-7-(4-carboxypiperidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The reaction was performed essentially as in example 64 but using thebenzyl ester of 4-carboxypiperidine in step a. instead of the dibenzylester of aspartic acid. The compound was further characterised andtested as the N-methyl-D-glucamine salt. Found: C, 64.29; H, 8.05; N,5.14. C₄₂ H₅₇ N₃ O₉. 2.0H₂ O requires C, 64.35; H, 7.84; N, 5.36%

EXAMPLE 141

Preparation ofcis-7-(2-S-(carboxymethyl)-pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The reaction was performed essentially as in example 64 but using thebenzyl ester of 2-S-carboxymethylpyrrolidine (prepared as in WO92/00295) in step a. instead of the dibenzyl ester of aspartic acid,α!^(D) =-22.0° (c=1.0 in methanol). The compound was furthercharacterised and tested as the N-methyl-D-glucamine salt. Found: C,61.76; H, 7.89; N, 5.31. C₄₂ H₅₇ N₃ O₉. 3.7H₂ O requires C, 61.91; H,7.97; N, 5.16%

EXAMPLE 142

Preparation ofcis-7-(2-R-(carboxymethyl)-pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The reaction was performed essentially as in example 64 but using thebenzyl ester of 2-R-carboxymethylpyrrolidine (prepared as in WO92/00295) in step a. instead of the dibenzyl ester of aspartic acid,α!^(D) =+18.0° (c=1.0 in methanol). The compound was furthercharacterised and tested as the N-methyl-D-glucamine salt. Found: C,59.01; H, 8.12; N, 5.49. C₄₂ H₅₇ N₃ O₉. 5.9H₂ O requires C, 59.07; H,8.12; N, 4.92%

EXAMPLE 143

Preparation ofcis-7-(2-S-(methoxycarbonylmethyl)pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The compound was prepared essentially as in example 63 using the productof example 141 as substrate instead ofcis-7-(1-S-carboxyl-2-methylpropylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane, α!^(D) =-21.0° (c=2.0 in CHCl3). Found: C, 75.80; H, 7.49;N, 4.62. C₃₆ H₄₂ N₂ O₄. 0.3 H₂ O requires C, 75.62; H, 7.50; N, 4.90%

EXAMPLE 144

Preparation ofcis-7-(2-R-(methoxycarbonylmethyl)pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The compound was prepared essentially as in example 63 using the productof example 142 as substrate instead ofcis-7-(1-S-carboxyl-2-methylpropylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane, α!^(D) =+18.0° (c=2.0 in CHCl₃). Found: C, 76.48; H, 7.46;N, 5.05. C₃₆ H₄₂ N₂ O₄ requires C, 76.30; H, 7.47; N, 4.94%

EXAMPLE 145

Preparation ofcis-7-(2R-(1S-carboxyethylaminocarbonyl)pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereomer 1

The compound was prepared essentially as in example 64 but using thebenzyl ester of D-prolyl-L-alanine in step a. instead of the dibenzylester of aspartic acid. The diastereomers were separated at the benzylester stage by column chromatography (silica 60% dichloromethane and 40%ethyl acetate). The compound with the higher R_(f) was converted to thetitle compound by hydrogenation. The compound was tested as theN-methyl-D-glucamine salt.

EXAMPLE 146

Preparation ofcis-7-(2R-(1S-carboxyethylaminocarbonylmethyl)pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereomer 2

The compound was prepared essentially as in example 145 but using thecompound with lower R_(f) after diastereomer separation in the finalhydrogenation step. The compound was tested as the N-methyl-D-glucaminesalt.

EXAMPLE 147

Preparation ofcis-7-(2R-(1R-carboxyethylaminocarbonyl)pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereomer 1

The compound was prepared essentially as in example 64 but using thebenzyl ester of D-prolyl-D-alanine in step a. instead of the dibenzylester of aspartic acid. The diastereomers were separated at the benzylester stage by column chromatography (silica 60% dichloromethane and 40%ethyl acetate). The compound with the higher R_(f) was converted to thetitle compound by hydrogenation. The compound was further characterisedand tested as the N-methyl-D-glucamine salt. Found: C, 59.62; H, 8.06;N, 6.23. C₄₄ H₆₀ N₄ O₁₀ 4.7H₂ O requires C, 59.45; H, 7.86; N, 6.30%

EXAMPLE 148

Preparation ofcis-7-(2R-(1R-carboxyethylaminocarbonyl)pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereomer 2

The compound was prepared essentially as in example 147 but using thecompound with lower R_(f) after diastereomer separation in the finalhydrogenation step. The compound was tested as the N-methyl-D-glucaminesalt.

EXAMPLE 149

Preparation ofcis-7-(2R-carboxy-4-S-hydroxypyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The compound was prepared essentially as in example 64 but using thebenzyl ester of trans hydroxy-D-proline in step a. instead of thedibenzyl ester of aspartic acid. The compound was further characterisedand tested as the N-methyl-D-glucamine salt. Found: C, 65.63; H, 7.48;N, 5.38. C₄₁ H₅₅ N₃ O₁₀ requires C, 65.67; H, 7.39; N, 5.38%

EXAMPLE 150

Preparation ofcis-7-(3-carboxy-pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The compound was prepared essentially as in example 64 but using thebenzyl ester of 3-carboxypyrrolidine (prepared as in WO 92/00295) instep a. instead of the dibenzyl ester of aspartic acid. The compound wasfurther characterised and tested as the N-methyl-D-glucamine salt.Found: C, 65.33; H, 7.67; N, 5.48. C₄₁ H₅₅ N₃ O₉. 1.4 H₂ O requires C,65.27; H, 7.65; N, 5.57%

EXAMPLE 151

Preparation ofcis-7-(3-methoxycarbonylpyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The compound was prepared essentially as in example 63 using the productof example 150 as substrate instead ofcis-7-(1-S-carboxyl-2-methylpropylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane. Found: C, 75.83; H, 7.41; N, 5.08. C₃₅ H₄₀ N₂ O₄ requiresC, 76.06; H, 7.29; N, 5.07%

EXAMPLE 152

Preparation ofcis-7-(3-(+)-ethoxycarbonylpiperidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The compound was prepared essentially as in example 64 but using(+)ethyl nipecotate (prepared as described in J. Neurochem., 1976 26,1029) in step a. instead of the dibenzyl ester of aspartic acid to givethe title compound directly without the need for subsequentdeprotection. Found: C, 76.69; H, 7.64; N, 4.81. C₃₇ H₄₄ N₂ O₄ requiresC, 76.52; H, 7.63; N, 4.82%

EXAMPLE 153

Preparation ofcis-7-(3-(-)-ethoxycarbonylpiperidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The compound was prepared essentially as in example 64 but using(-)ethyl nipecotate in step a. instead of the dibenzyl ester of asparticacid to give the title compound directly without the need for subsequentdeprotection. Found: C, 76.29; H, 7.61; N, 4.68. C₃₇ H₄₄ N₂ O₄ requiresC, 76.52; H, 7.63; N, 4.82%

EXAMPLE 154

Preparation ofcis-7-(3-(+)-methoxycarbonylpiperidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereomer 1

a.cis-7-(3-(+)-carboxy-piperidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (separated diastereomers)

The compound was prepared essentially as in example 64 but using(+)benzyl nipecotate (prepared by standard means from (+) ethylnipecotate) in step a. instead of the dibenzyl ester of aspartic acid togive the carboxylic acid as a mixture of diastereomers. The twodiastereomers were separated by chromatography (silica 90%dichloromethane and 10% ethyl acetate).

b.cis-7-(3-(+)-methoxycarbonyl-piperidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereomer 1

The compound was prepared essentially as in example 63 using the lesspolar (higher R_(f) material) isolated in step a. above as substrateinstead ofcis-7-(1-S-carboxyl-2-methylpropylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane.

EXAMPLE 155

Preparation ofcis-7-(3-(+)-methoxycarbonylpiperidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereomer 2

The compound was prepared essentially as in example 63 using the morepolar (lower R_(f) material) isolated in step a. of example 154 assubstrate instead ofcis-7-(1-S-carboxyl-2-methylpropylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane.

EXAMPLE 156

Preparation ofcis-7-(3-(-)-methoxycarbonylpiperidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereomer 1

The compound was prepared essentially as in example 154 but using (-)benzyl nipecotate as substrate in step a. rather than (+) benzylnipecotate. As in that example the less polar material was converted tothe title compound in step b.

EXAMPLE 157

Preparation ofcis-7-(3-(-)-methoxycarbonylpiperidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereomer 2

The compound was prepared essentially as in example 63 using the morepolar (lower R_(f) material) isolated in step a. of example 156 assubstrate instead ofcis-7-(1-S-carboxyl-2-methylpropylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane.

EXAMPLE 158

Preparation ofcis-7-(2R-(1methyl-1-carboxycyclopropylaminocarbonyl)pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereomer 1

The compound was prepared essentially as in example 64 but using thebenzyl ester of D-prolyl-cyclopropylalanine (prepared by standard means)in step a. instead of the dibenzyl ester of aspartic acid. Thediastereomers were separated at the benzyl ester stage by columnchromatography (silica 60% dichloromethane and 40% ethyl acetate). Thecompound with the higher R_(f) was converted to the title compound byhydrogenation, α!^(D) =+10.0° (c=1.0 in methanol). The compound wasfurther characterised and tested as the N-methyl-D-glucamine salt.Found: C, 58.54; H, 7.44; N, 6.03. C₄₅ H₆₀ N₄ O₁₀ 5.6H₂ O requires C,58.92; H, 7.81; N, 6.11%

EXAMPLE 159

Preparation ofcis-7-(2R-(1methyl-1-carboxycyclopropylaminocarbonyl)pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereomer 2

The compound was prepared essentially as in example 158 but using thecompound with lower R_(f) after diastereomer separation in the finalhydrogenation step. The compound was tested as the N-methyl-D-glucaminesalt.

EXAMPLE 160

Preparation ofcis-7-(2-R-carboxypyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3-(2-fluorobenzo)-5,6-benzobicyclo2.2.2!octane (mixture of isomers 1)

a. 2,3-(2-fluorobenzo)-5,6-benzobicyclo 2.2.2!octane-7,8-dicarboxylicanhydride

This was performed essentially as described in example 1 step a. exceptthat 2-fluoroanthracene was used as reactant instead of anthracene.

b.8-(1-adamantylmethylaminocarbonyl)-2,3-(2-fluorobenzo)-5,6-benzobicyclo2.2.2!octane-7-carboxylic acid.

The reaction was performed essentially as described in example 14 butusing the compound described in step a. above rather than2,3,5,6-dibenzobicyclo 2.2.2!octane-7,8-dicarboxylic anhydride.

c.cis-7-(2-R-benzyloxycarbonylpyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3-(2-fluorobenzo)-5,6-benzobicyclo2.2.2!octane.

The reaction was performed essentially as in example 46 but using thecompound prepared in step b above, rather than(+)cis-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane-7-carboxylic acid.

d.cis-7-(2-R-carboxypyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3-(2-fluorobenzo)-5,6-benzobicyclo2.2.2!octane (mixture of isomers 1)

The reaction was performed essentially as in example 48 but using thecompound prepared in step c above, rather thancis-7-(2-R-benzyloxycarbonylpyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane. The material which by this stage was a mixture of eightcompounds was separated by HPLC (C8 column 60% acetonitrile, 40% waterand 0.1% acetic acid) into three components. The material with aretention time of 15 min was designated the compound of this example.The compound was further characterised and tested as theN-methyl-D-glucamine salt found: C, 65.22; H, 7.38; N, 5.42. C₄₁ H₅₄ FN₃O₉ requires C, 65.49; H, 7.24; N, 5.59%

EXAMPLE 161

Preparation ofcis-7-(2-R-carboxypyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3-(2-fluorobenzo)-5,6-benzobicyclo2.2.2!octane (mixture of isomers 2)

The mixture from example 160 step d with a retention time of 16 min wasdesignated the compound of this example. The compound was furthercharacterised and tested as the N-methyl-D-glucamine salt found: C,64.99; H, 7.29; N, 5.59. C₄₁ H₅₄ FN₃ O₉ requires C, 65.49; H, 7.24; N,5.59%

EXAMPLE 162

Preparation ofcis-7-(2-R-carboxypyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3-(2-fluorobenzo)-5,6-benzobicyclo2.2.2!octane (mixture of isomers 3)

The mixture from example 160 step d with a retention time of 22 min wasdesignated the compound of this example. The compound was furthercharacterised and tested as the N-methyl-D-glucamine salt found: C,65.29; H, 7.42; N, 5.65. C₄₁ H₅₄ FN₃ O₉ requires C, 65.49; H, 7.24; N,5.59%

EXAMPLE 163

Preparation ofcis-7-(2R-(1-carboxy-1-methylethylaminocarbonyl)pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereomer 1

The compound was prepared essentially as in example 64 but using thebenzyl ester of D-prolyl-alpha-aminobutyric acid in step a. instead ofthe dibenzyl ester of aspartic acid. The diastereomers were separated atthe benzyl ester stage by recrystallisation from ethyl acetate andcolumn chromatography (silica 50% hexane and 50% ethyl acetate). Thecompound with the lower R_(f) was converted to the title compound byhydrogenation. The compound was further characterised and tested as theN-methyl-D-glucamine salt. Found: C, 65.91; H, 7.65; N, 6.60. C₄₅ H₆₂ N₄O₁₀ requires C, 65.99; H, 7.63; N, 6.84%

EXAMPLE 164

Preparation ofcis-7-(2R-(1-carboxy-1-methylethylaminocarbonyl)pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereomer 2

The compound was prepared essentially as in example 147 but using thecompound with higher R_(f) after diastereomer separation in the finalhydrogenation step. The compound was tested as the N-methyl-D-glucaminesalt.

EXAMPLE 165

Preparation ofcis-7-(2-R-carboxypyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-8-fluoro-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The compound was prepared essentially as described in example 160 butperforming the reaction in step a. with anthracene and 2-fluoromaleicanhydride (prepared as in J.Am.Chem.Soc., 1959, 81, 2678) instead of thereagents stated. No attempt was made at separation of the diastereomersat any stage. The compound was further characterised and tested as theN-methyl-D-glucamine salt found: C, 65.59; H, 7.18; N, 5.61. C₄₁ H₅₄ FN₃O₉ requires C, 65.49; H 7.24; N, 5.59%

EXAMPLE 166

Preparation ofcis-7-(-N-(carboxymethyl)-N-(methoxycarbonylmethyl)aminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane

The reaction was performed essentially as in example 25 but using methylN-(carboxymethyl)glycine (prepared as in Tetrahedron, 1984, 40, 1151) assubstrate instead of L-alanine methyl ester. The compound was furthercharacterised and tested as the N-methyl-D-glucamine salt found: C,64.21; H, 7.25; N, 5.22. C₄₁ H₅₅ N₃ O₁₁ requires C, 64.30; H, 7.24; N,5.49%

EXAMPLE 167

Preparation of cis-7-(-N-(4-(2-oxo-N(carboxymethyl)pyrrolidine))aminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereomers 1 and 2

The reaction was performed essentially as in example 64 but using thebenzyl ester of N-carboxymethyl-2-oxo-4-aminopyrrolidine (prepared as inPeptide Research 1991, 4, 171) in step a. instead of the dibenzyl esterof aspartic acid. The compound was separated at the end of step a. intotwo pairs of diastereoisomer by column chromatography the higher R_(f)components being hydrogenated at step b to give the title compounds ofthis example. The compound was further characterised and tested as theN-methyl-D-glucamine salt. Found: C, 57.23; H, 7.41; N, 6.13. C₄₂ H₅₆ N₄O₁₀ 5.5H₂ O requires C, 57.54; H, 7.71; N, 6.39%

EXAMPLE 168

Preparation of cis-7-(-N-(4-(2-oxo-N-(carboxymethyl)pyrrolidine))aminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereomers 3 and 4

The reaction was performed essentially as in example 167 except that thelower R_(f) components were used in the hydrogenation step b. Thecompound was further characterised and tested as theN-methyl-D-glucamine salt. Found: C, 56.07; H, 7.39; N, 6.56. C₄₂ H₅₆ N₄O₁₀ 6.5H₂ O requires C, 56.46; H, 7.78; N, 6.27%

EXAMPLE 169

Preparation ofcis-7-(-N-(4-(2-oxo-N-(methoxycarbonylmethyl)pyrrolidine))aminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereomers 1 and 2

The compound was prepared essentially as in example 63 using thecompound of example 167 as substrate instead ofcis-7-(1-S-carboxyl-2-methylpropylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane. Found: C, 66.83; H, 7.21; N, 6.15. C₃₆ H₄₁ N₃ O₅. 1.7CH₃OH and 0.4 Ch₂ Cl₂ requires C, 66.89; H, 7.21; N, 6.15%

EXAMPLE 170

Preparation ofcis-7-(-N-(4-(2-oxo-N-(methoxycarbonylmethyl)pyrrolidine))aminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereomers 3 and 4

The compound was prepared essentially as in example 63 using thecompound of example 167 as substrate instead ofcis-7-(1-S-carboxyl-2-methylpropylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane. Found: C, 64.05; H, 6.71; N, 5.82. C₃₆ H₄₁ N₃ O₅. 1.0CH₃OH and 1.0 CH₂ Cl₂ requires C, 64.04; H, 6.65; N, 5.90% H, 6.71; N,5.82. C₃₆ H₄₁ N₃ O₅. 1.0CH₃ OH and 1.0 CH₂ Cl₂ requires C, 64.04; H,6.65; N, 5.90%

EXAMPLE 171

Preparation ofcis-7-(1S-(carboxymethylaminocarbonyl)-2-phenylethylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The reaction was performed essentially as in example 64 but using thebenzyl ester of L-phenylalanylglycine in step a. instead of the dibenzylester of aspartic acid. The compound was further characterised andtested as the N-methyl-D-glucamine salt. Found: C, 64.11; H, 7.62; N,6.35. C₄₇ H₆₀ N₄ O₁₀. 2.3H₂ O requires C, 63.95; H, 7.38; N, 6.35%

EXAMPLE 172

Preparation ofcis-7-(1S-(1R-carboxyethylaminocarbonyl)-2-phenylethylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The reaction was performed essentially as in example 64 but using thebenzyl ester of L-phenylalanyl-D-alanine in step a. instead of thedibenzyl ester of aspartic acid. The compound was tested as themono-N-methyl-D-glucamine salt.

EXAMPLE 173

Preparation ofcis-7-(1R-(carboxymethylaminocarbonyl)-2-phenylethylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The reaction was performed essentially as in example 64 but using thebenzyl ester of D-phenylalanylglycine in step a. instead of the dibenzylester of aspartic acid. The compound was further characterised andtested as the mono-N-methyl-D-glucamine salt. Found: C, 62.18; H, 7.48;N, 5.74. C₄₇ H₆₀ N₄ O₁₀. 4.OH₂ O requires C, 61.86; H, 7.51; N, 6.14%

EXAMPLE 174

Preparation ofcis-7-(1S-(carboxymethylaminocarbonyl)-2-(3-indolyl)phenylethylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The reaction was performed essentially as in example 64 but using thebenzyl ester of L-tryptophanylglycine in step a. instead of the dibenzylester of aspartic acid. The compound was further characterised andtested as the mono-N-methyl-D-glucamine salt. Found: C, 58.88; H, 7.07;N, 6.62. C₄₉ H₆₁ N₅ O₁₀. 3.2H₂ O and 1.0 CH₂ Cl₂ requires C, 58.73; H,6.84; N, 6.85%

EXAMPLE 175

Preparation ofcis-7-(2R-(1-S-carboxy-2-carboxyethylaminocarbonyl)pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereomer 1

The compound was prepared essentially as in example 64 but using thedibenzyl ester of D-prolyl-L-aspartic acid in step a. instead of thedibenzyl ester of aspartic acid. The diastereomers were separated at thebenzyl ester stage by column chromatography (silica 60% dichloromethaneand 40% ethyl acetate). The compound with the higher R_(f) was convertedto the title compound by hydrogenation. Found: C, 64.46; H, 6.97; N,5.30. C₃₈ H₄₃ N₃ O₇.3.0 H₂ O requires C, 64.48; H, 6.97; N, 5.63% ¹ HNMR

EXAMPLE 176

Preparation ofcis-7-(2R-(1-S-carboxy-2-carboxyethylaminocarbonyl)pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereomer 2

The compound was prepared essentially as in example 175 but using thecompound with lower R_(f) after diastereomer separation in the finalhydrogenation step. Found: C, 69.21; H, 6.73; N, 5.93. C₃₈ H₄₃ N₃ O₇.0.5 H₂ O requires C, 68.86; H, 6.69; N, 6.34%

EXAMPLE 177

Preparation of (±)-cis-8-(6-undecylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane-7-carboxylic acid

The compound was prepared essentially as in example 14 but using6-undecylamine as substrate instead of 1-adamantylmethylamine. Thecompound was further characterised and tested as theN-methyl-D-glucamine salt. Found: C, 65.38; H, 8.53; N, 5.33. C₃₆ H₅₄ N₂O₈. 1.0H₂ O requires C, 65.43; H, 8.54; N, 4.23%

EXAMPLE 178

Preparation of cis-7-(-N-(3S-(2-oxo-N-(carboxymethyl)pyrrolidine))aminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane

The reaction was performed essentially as in example 64 but using thebenzyl ester of N-carboxymethyl-2-oxo-3S-aminopyrrolidine (prepared asin J. Org. Chem. 1982, 47, 105) in step a. instead of the dibenzyl esterof aspartic acid. The compound was tested as the N-methyl-D-glucaminesalt.

EXAMPLE 179

Preparation of cis-7-(-N-(3R-(2-oxo-N-(carboxymethyl)pyrrolidine))aminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane

The reaction was performed essentially as in example 64 but using thebenzyl ester of N-carboxymethyl-2-oxo-3R-aminopyrrolidine (prepared asin J. Org. Chem. 1982, 47, 105) in step a. instead of the dibenzyl esterof aspartic acid. The compound was tested as the N-methyl-D-glucaminesalt.

EXAMPLE 180

Preparation ofcis-7-(2R-(carboxymethylaminocarbonyl)-2S-methyl-pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane

The compound was prepared essentially as in example 64 but using thebenzyl ester of α-methyl-D-prolyl-glycine (prepared as in J. Am. Chem.Soc., 1983, 105, 5390) in step a. instead of the dibenzyl ester ofaspartic acid. The compound was tested as the N-methyl-D-glucamine salt.

EXAMPLE 181

Preparation ofcis-7-(2R-(aminocarbonylmethylaminocarbonyl)-pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane

The compound was prepared essentially as in example 64 but usingD-prolyl-glycinamide in step a. instead of the dibenzyl ester ofaspartic acid to give the title compound directly. Obviously there wasno need for a hydrogenation step. Found: C, 67.41; H, 7.01; N, 8.54. C₃₆H₄₂ N₄ O₄. 2.4H₂ O requires C, 67.79; H, 7.39; N, 8.78%

EXAMPLE 182

Preparation ofcis-7-(1R-(aminocarbonylmethylaminocarbonyl)-phenethylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane

The compound was prepared essentially as in example 64 but usingD-phenylalanyl-glycinamide in step a. instead of the dibenzyl ester ofaspartic acid to give the title compound directly. Obviously there wasno need for a hydrogenation step. Found: C, 71.76; H, 7.01; N, 8.09. C₄₀H₄₄ N₄ O₄. 1.5H₂ O requires C, 71.51; H, 7.05; N, 8.33%

EXAMPLE 183

Preparation ofcis-7-(2R-(carboxymethylaminocarbonyl)-4R-hydroxy-pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane

The compound was prepared essentially as in example 64 but using thebenzyl ester of cis-4-hydroxy-D-prolylglycine in step a. instead of thedibenzyl ester of aspartic acid. The compound was further characterisedand tested as the N-methyl-D-glucamine salt. Found: C, 56.39; H, 7.65;N, 7.96. C₄₃ H₅₈ N₄ O₁₁. 6.2H₂ O and 1.6 CH₃ CN requires C, 56.37; H,7.70; N, 7.97%

EXAMPLE 184

Preparation of cis-7-(2S-(1S-carboxyethylaminocarbonylmethyl)pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

a. cis-7-(2S-(11S-benzyloxycarbonylethylaminocarbonylmethyl)-pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The compound of example 141 (250 mg, 0.45 mmol) was dissolved indichloromethane (30 ml) and L-alanine benzyl ester p-toluenesulphonatesalt (160 mg, 0.45 mmol) was added followed by PyBOP (235 mg, 0.45 mmol)and Hunigs base (240 ml, 1.35 mmol). The mixture was stirred at roomtemperature for 42 h and then washed with 5% potassium hydrogensulphatesolution (15 ml), sodium hydrogencarbonate solution (15 ml) andsaturated brine (15 ml). The solution was then dried and the productpurified by chromatography (silica and ethyl acetate) to yield acolourless solid.

b.cis-7-(2S-(1S-carboxyethylaminocarbonylmethyl)-pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The reaction was performed essentially as in example 48 but using theproduct of step a. as substrate instead of the product of example 46.The compound was tested as the N-methyl-D-glucamine salt.

EXAMPLE 185

Preparation ofcis-7-(2S-(1R-carboxyethylaminocarbonylmethyl)pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The reaction was performed essentially as in example 184 but usingD-alanine benzyl ester p-toluenesulphonate salt in step a. rather thanL-alanine benzyl ester p-toluenesulphonate salt. The compound wasfurther characterised and tested as the N-methyl-D-glucamine salt.Found: C, 59.20; H, 7.64; N, 6.11. C₄₅ H₆₂ N₄ O₁₁. 4.9H₂ O requires C,59.54; H, 7.98; N, 6.17%

EXAMPLE 186

Preparation ofcis-7-(2S-(1R-carboxyethylaminocarbonylmethyl)pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereomer 1

a.cis-7-(2S-carboxymethylpyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereomer 1

The compound of example 141 was separated into its constituentdiastereomers by recrystallisation from dichloromethane. The crystalsisolated were the title compound. In addition the other diastereomer wasisolated by concentration of the mother liquors.

b.cis-7-(2S-(1R-carboxyethylaminocarbonylmethyl)pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereomer 1

This was prepared in two steps as described in example 185 but using theproduct from step a. above rather than the compound of example 141 asthe substrate in step a. The compound was tested as theN-methyl-D-glucamine salt.

EXAMPLE 187

Preparation ofcis-7-(2S-(1R-carboxyethylaminocarbonylmethyl)pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereomer 2

This was prepared essentially as in example 185 but using thedichloromethane soluble diastereomer described in example 186 step a. assubstrate in step a. rather than the compound of example 141. Thecompound was tested as the N-methyl-D-glucamine salt.

EXAMPLE 188

Preparation ofcis-7-(2R-(methoxycarbonylmethylaminocarbonyl)pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereomer 1

The compound of example 123 was separated into its constituentdiastereomers by chromatography (silica 30% ethyl acetate and 70%dichloromethane). The less polar material was designated the compound ofthis example. Found: C, 64.59; H, 6.76: N, 5.94. C₃₇ H₄₃ N₃ O₅.0.3 EtOAcand 1.1 CH₂ Cl₂ requires C, 64.70; H, 6.58; N, 5.76%

EXAMPLE 189

Preparation ofcis-7-(2R-(methoxycarbonylmethylaminocarbonyl)pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane.

The more polar material isolated in example 188 was designated thecompound of this example. Found: C, 70.27; H, 7.70; N, 6.63. C₃₇ H₄₃ N₃O₅ requires C, 69.97; H, 7.27; N, 6.62%

EXAMPLE 190

Preparation ofcis-7-(2R-(carboxymethyl(N-methyl)aminocarbonyl)pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The compound was prepared essentially as in example 64 but using thebenzyl ester of D-prolyl-sarcosine in step a. instead of the dibenzylester of aspartic acid. The compound was tested as theN-methyl-D-glucamine salt.

EXAMPLE 191

Preparation ofcis-7-(-N-(3R-(2-oxo-N-(methoxycarbonylmethyl)pyrrolidine))aminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane

The reaction was performed essentially as in example 63 using thecompound of example 179 as substrate instead ofcis-7-(1-S-carboxyl-2-methylpropylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane. The compound was tested as the N-methyl-D-glucamine salt.

EXAMPLE 192

Preparation ofcis-7-(2-R-carboxy-pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-1,4-dimethyl-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereomer 1

The compound was prepared essentially as in example 137 but using9,10-dimethylanthracene as substrate in step a. instead of9,10-difluoroanthracene. In addition the mixture of diastereomersisolated after step c was separated into its constituent isomers usingchromatography (silica 10% ethyl acetate and 90% dichloromethane). Theless polar material was taken through to the title compound. Thecompound was further characterised and tested as theN-methyl-D-glucamine salt found: C, 64.71; H, 7.88; N, 5.06. C₄₃ H₅₉ N₃O₉. 2.0H₂ O requires C, 64.65; H, 7.96; N, 5.26%

EXAMPLE 193

Preparation ofcis-7-(2-R-carboxy-pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-1,4-dimethyl-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereomer 2

The more polar compound described in example 192 was hydrogenated togive the compound of this example. The compound was furthercharacterised and tested as the N-methyl-D-glucamine salt. Found: C,61.67; H, 7.88; N, 4.82. C₄₃ H₅₉ N₃ O₉. 4.0H₂ O requires C, 61.88; H,8.10; N, 5.04

EXAMPLE 194

Preparation ofcis-7-(2S-(carboxymethylaminocarbonylmethyl)pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The reaction was performed essentially as in example 184 but using thebenzyl ester of glycine in step a. rather than L-alanine benzyl esterp-toluenesulphonate salt. The compound was further characterised andtested as the N-methyl-D-glucamine salt, HPLC; R_(T) =16.2 mins, C8column, CH₃ CN 50%, 0.1% CH₃ COOH.

EXAMPLE 195

Preparation ofcis-7-(2R-(1R-(2,2-dimethyl-1,3-dioxolane-4-methoxycarbonyl)-ethylaminocarbonyl)pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane

The compound of example 147 (305 mg, 0.5 mmol) was dissolved in drydichloromethane (3 ml) and solketal (66 ml, 0.5 mmol) was added. DMAP (2mg) and DCCI (103 mg, 0.5 mmol) were added and the reaction mixturestirred at room temperature for 1 h. After filtration the solution wasevaporated to leave a foam which was purified by column chromatography(silica 95% dichloromethane and 5% methanol) to leave the title compound(195 mg). Found: C, 71.42; H, 7.45; N, 5.84. C₄₃ H₅₃ N₃ O₇ requires C,71.35; H, 7.38; N, 5.81%

EXAMPLE 196

Preparation ofcis-7-(2R-(1R-(pivaloyloxymethoxycarbonyl)-ethylaminocarbonyl)pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane

The compound of example 147 (305 mg, 0.5 mmol) was dissolved in DMF (2ml) and pivaloyloxymethyl chloride (72 ml, 0.55 mmol) and caesiumcarbonate (82 mg, 0.5 mmol) was added. After gentle warming the reactionwas stirred at room temperature for 1 h. The reaction mixture was pouredonto brine (30 ml) and extracted with ethyl acetate (30 ml). The organiclayer was washed with brine (2×30 ml) dried and evaporated. The materialwas completely purified by passage through a silica pad eluting with a1:1 mixture of dichloromethane and ethyl acetate to leave the titlecompound (160 mg). Found: C, 71.21; H, 7.48; N, 5.62. C₄₃ H₅₃ N₃ O₇requires C, 71.35; H, 7.38; N, 5.81%

EXAMPLE 197

Preparation ofcis-7-(2R-aminocarbonyl)pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The compound was prepared essentially as in example 25 but usingD-prolinamide instead of the methyl ester of 1-alanine.

EXAMPLE 198

Preparation ofcis-7-(2R-(carboxymethylaminocarbonylmethyl)pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereomer 1

a.cis-7-(2R-carboxymethylpyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (separation of diastereomers)

The compound of example 142 was treated with dichloromethane. Thedichloromethane insoluble material was designated diastereomer 1 and thesoluble isomer designated diastereomer 2

b.cis-7-(2-(carboxymethylaminocarbonylmethyl)-pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereomer 1

The compound was prepared essentially as in example 194 except that thediastereomer 1 from step a. above was used as substrate instead of thecompound of example 141. The compound was tested as theN-methyl-D-glucamine salt.

EXAMPLE 199

Preparation ofcis-7-(2R-(carboxymethylaminocarbonylmethyl)pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereomer 2

The compound was prepared essentially as in example 194 except that thediastereomer 2 from example 198 step a. was used as substrate instead ofthe compound of example 141. The compound was tested as theN-methyl-D-glucamine salt.

EXAMPLE 200

Preparation ofcis-7-(2R-(1S-carboxyethylaminocarbonylmethyl)pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereomer 1

The compound was prepared essentially as in example 184 except that thediastereomer 1 from example 198 step a. was used as substrate instead ofthe compound of example 141. The compound was tested as theN-methyl-D-glucamine salt.

EXAMPLE 201

Preparation ofcis-7-(2R-(1S-carboxyethylaminocarbonylmethyl)pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereomer 2

The compound was prepared essentially as in example 184 except that thediastereomer 2 from example 198 step a. was used as substrate instead ofthe compound of example 141. The compound was tested as theN-methyl-D-glucamine salt.

EXAMPLE 202

Preparation ofcis-7-(2R-(1R-carboxyethylaminocarbonylmethyl)pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereomer 1

The compound was prepared essentially as in example 185 except that thediastereomer 1 from example 198 step a. was used as substrate instead ofthe compound of example 141. The compound was tested as theN-methyl-D-glucamine salt.

EXAMPLE 203

Preparation ofcis-7-(2R-(1R-carboxyethylaminocarbonylmethyl)pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereomer 2

The compound was prepared essentially as in example 185 except that thediastereomer 2 from example 198 step a. was used as substrate instead ofthe compound of example 141. The compound was tested as theN-methyl-D-glucamine salt.

EXAMPLE 204

Preparation ofcis-7-(2R-(carboxyethyl)pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The compound was prepared essentially as in example 64 but using thebenzyl ester of trans-3-(2R-pyrrolidino)-but-2-enoic acid (prepared frombenzyl(triphenylphosphoranylidene)acetate andN-(t-butoxycarbonyl)-D-prolinal by Wittig reaction) in step a. insteadof the dibenzyl ester of aspartic acid. The compound was furthercharacterised and tested as the N-methyl-D-glucamine salt. Found: C,64.81; H, 7.94; N, 5.14. C₄₃ H₅₉ N₃ O₉. 2.0H₂ O requires C, 64.77; H,7.96; N, 5.27%

EXAMPLE 205

Preparation ofcis-7-(2S-(methoxycarbonylethenyl)pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The compound was prepared essentially as in example 25 but using themethyl ester of trans-3-(2S-pyrrolidino)-but-2-enoic acid (prepared frommethyl(triphenylphosphoranylidene)acetate andN-(t-butoxycarbonyl)-L-prolinal by Wittig reaction) instead of L-alaninemethyl ester. Found: C, 76.66; H, 7.39; N, 4.73. C₃₇ H₄₂ N₂ O₄ requiresC, 76.79; H, 7.32; N, 4.84%

EXAMPLE 206

Preparation ofcis-7-(2S-(methoxycarbonylethyl)pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

This was prepared by treating the compound of example 205 with 10%palladium on charcoal in an atmosphere of hydrogen gas. Found: C, 76.73;H, 7.79; N, 4.91. C₃₇ H₄₄ N₂ O₄ requires C, 76.52; H, 7.64; N, 4.82%

EXAMPLE 207

Preparation ofcis-7-(1S-(aminocarbonylmethylaminocarbonyl)-2-phenylethylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereomer 1

The reaction was performed essentially as in example 25 but usingL-phenylalanylglycinamide as substrate instead of L-alanine methylester. The mixture of diastereomers produced by this reaction wasseparated by column chromatography (silica and ethyl acetate). The lesspolar material was designated the title compound of this example. Found:C, 72.24; H, 7.02; N, 8.21. C₄₀ H₄₄ N₄ O₄.1.2 H₂ O requires C, 74.50; H,6.87; N, 8.68%

EXAMPLE 208

Preparation ofcis-7-(1S-(aminocarbonylmethylaminocarbonyl)-2-phenylethylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereomer 2

The more polar material isolated from the separation in example 207 wasdesignated the compound of this example. Found: C, 72.12; H, 6.95; N,8.39. C₄₀ H₄₄ N₄ O₄.1.2 H₂ O requires C, 74.50; H, 6.87; N, 8.68%

EXAMPLE 209

Preparation of(±)-7-(1-adamantylmethylaminocarbonylmethyl)-2,3,5,6-dibenzobicyclo2.2.2!octane-7-carboxylic acid

The compound was prepared essentially as in example 131 except thatitaconic anhydride was used as substrate instead of the methyl ester ofaconitic anhydride in step a. The compound was further characterised andtested as the N-methyl-D-glucamine salt, m.p. 115°-120° . Found: C,68.06; H, 7.71; N, 4.37. C₃₇ H₅₀ N₂ O₈ requires C, 68.29; H, 7.74; N,4.30%

EXAMPLE 210

Preparation of7-(1S-methoxycarbonylethylaminocarbonyl)-7-(1-adamantylmethylaminocarbonylmethyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereoisomers)

The compound was prepared essentially as in example 25 except that thecompound of example 209 was used as substrate instead of the compound ofexample 14. Found: C, 75.36; H, 7.56; N, 4.99. C₃₄ H₄₀ N₂ O₄ requires C,75.53; H, 7.46; N, 5.18%

EXAMPLE 211

Preparation of7-(2R-carboxypyrrolidinocarbonyl)-7-(1-adamantylmethylaminocarbonylmethyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereoisomers)

The compound was prepared essentially as in example 160 except that thecompound of example 209 was used in step c as substrate instead of thecompound of example 160 step b. The compound was further characterisedand tested as the N-methyl-D-glucamine salt. Found: C, 67.24; H, 7.74;N, 5.81. C₄₂ H₅₇ N₃ O₉ requires C, 67.45; H, 7.68; N, 5.62%

EXAMPLE 212

Preparation of(±)-cis-7-(2-carboxycyclopentylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers 1)

The compound was prepared essentially as in example 64 but using thebenzyl ester of cis 2-amino-cyclopentanoic acid in step a. instead ofthe dibenzyl ester of aspartic acid. The mixture of compounds after stepa. was separated by column chromatography (silica 85% dichloromenthane15% ethyl acetate) to give two pairs of diastereomers. The less polarmaterial was hydrogenated to give the compound of this example. Thecompound was further characterised and tested as theN-methyl-D-glucamine salt. Found: C, 65.12; H, 7.75; N, 5.42. C₄₂ H₅₇ N₃O₉.1.5 H₂ O requires C, 65.1; H, 7.80; N, 5.42%

EXAMPLE 213

Preparation of(±)-cis-7-(2-carboxycyclopentylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers 2)

The compound was prepared essentially as in example 212 except that themore polar material after separation was hydrogenated to give thecompound of this example. The compound was further characterised andtested as the N-methyl-D-glucamine salt. Found: C, 64.88; H, 7.91; N,5.28. C₄₂ H₅₇ N₃ O₉.1.7 H₂ O requires C, 64.8; H, 7.82; N, 5.40%

EXAMPLE 214

Preparation ofcis-7-(2R-(1R-methoxycarbonylethylaminocarbonyl)pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (single diastereomer)

The compound was prepared essentially as in example 63 except that thecompound of example 147 was used as substrate instead ofcis-7-(1-S-carboxyl-2-methylpropylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers). Found: C, 72.88; H, 7.51; N,6.58. C₃₈ H₄₅ N₃ O₅ requires C, 73.17; H, 7.27; N, 6.74%

EXAMPLE 215

Preparation ofcis-7-(2S-(carboxyethyl)pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The compound was prepared essentially as in example 64 but using thebenzyl ester of trans-3-(2S-pyrrolidino)-but-2-enoic acid (prepared frombenzyl(triphenylphosphoranylidene)acetate andN-(t-butoxycarbonyl)-L-prolinal by Wittig reaction) in step a. insteadof the dibenzyl ester of aspartic acid. The compound was furthercharacterised and tested as the N-methyl-D-glucamine salt. Found: C,66.64; H, 8.02; N, 5.60. C₄₃ H₅₉ N₃ O₉.0.6 H₂ O requires C, 66.80; H,7.85; N, 5.44%

EXAMPLE 216

Preparation ofcis-7-(1S-carboxy-(2-naphthyl)ethylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The compound was prepared essentially as in example 64 but using thebenzyl ester L-3-(2-naphthyl)alanine in step a. instead of the dibenzylester of aspartic acid. The compound was further characterised andtested as the N-methyl-D-glucamine salt. Found: C, 70.15; H, 7.33; N,5.05. C₄₉ H₅₉ N₃ O₉. 0.3 H₂ O requires C, 70.05; H, 7.16; N, 5.00%

EXAMPLE 217

Preparation ofcis-7-(1S-carboxy-(1-naphthyl)-ethylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The compound was prepared essentially as in example 64 but using thebenzyl ester L-3-(1-naphthyl)alanine in step a. instead of the dibenzylester of aspartic acid. The compound was further characterised andtested as the N-methyl-D-glucamine salt. Found: C, 69.94; H, 7.14; N,5.23. C₄₉ H₅₉ N₃ O₉. 0.3 H₂ O requires C, 70.05; H, 7.16; N, 5.00%

EXAMPLE 218

Preparation ofcis-7-(1R-(1R-carboxyethylaminocarbonyl)-2-phenylethylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The compound was prepared essentially as in example 64 but using thebenzyl ester D-phenylalanyl-D-alanine in step a. instead of the dibenzylester of aspartic acid. The compound was further characterised andtested as the N-methyl-D-glucamine salt. Found: C, 64.21; H, 7.63; N,6.36. C₄₈ H₆₂ N₄ O₁₀. 2.3 H₂ O requires C, 64.28; H, 7.63; N, 6.36%

EXAMPLE 219

Preparation ofcis-7-(3-S-carboxy-1,2,3,4-tetrahydroisoquinolinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The compound was prepared essentially as in example 64 but using thebenzyl ester 1,2,3,4-tetrahydroisoquinoline-3-S-carboxylic acid in stepa. instead of the dibenzyl ester of aspartic acid. The compound wasfurther characterised and tested as the N-methyl-D-glucamine salt.Found: C, 66.75; H, 7.37; N, 5.08. C₄₆ H₅₇ N₃ O₉₀. 1.7 H₂ O requires C,66.80; H, 7.37; N, 5.08%

EXAMPLE 220

Preparation of7-(2R-carboxypyrrolidinocarbonyl)-8-(1-adamantylmethyl-N-(methyl)aminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereoisomers)

a.(±)-8-(1-adamantylmethyl-N-(methyl)aminocarbonylmethyl)-2,3,5,6-dibenzobicyclo2.2.2!octane-7-carboxylic acid

This was prepared essentially as in example 14 except thatN-methyl-1-adamantanemethylamine was used as substrate instead of1-adamantanemethylamine.

b.7-(2R-benzyloxycarbonylpyrrolidinocarbonyl)-8-(1-adamantylmethyl-N-(methyl)aminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereoisomers)

This was prepared essentially as in example 46 except that the productof step a. was used as substrate instead of the product of example 14.

c.7-(2R-carboxypyrrolidinocarbonyl)-8-(1-adamantylmethyl-N-(methyl)aminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereoisomers)

This was prepared essentially as in example 48 except that the productof step b above was used as substrate instead of the product of example46. The compound was further characterised and tested as theN-methyl-D-glucamine salt. Found: C, 63.54; H, 7.87; N, 5.32. C₄₂ H₅₇ N₃O₉. 2.3 H₂ O requires C, 63.91; H, 7.87; N, 5.32%

EXAMPLE 221

Preparation of7-(2R-(carboxymethylaminocarbonyl)pyrrolidinocarbonyl)-8-(1-adamantylmethyl-N-(methyl)aminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereoisomers)

The compound was prepared essentially as in example 194 except that thecompound of example 220 was used as substrate instead of the compound ofexample 141 in step a. The compound was tested as theN-methyl-D-glucamine salt.

EXAMPLE 222

Preparation of7-(2R-(1S-carboxyethylaminocarbonyl)pyrrolidinocarbonyl)-8-(1-adamantylmethyl-N-(methyl)aminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereoisomers)

The compound was prepared essentially as in example 184 except that thecompound of example 220 was used as substrate instead of the compound ofexample 141 in step a. The compound was tested as theN-methyl-D-glucamine salt.

EXAMPLE 223

Preparation of7-(2R-(1R-carboxyethylaminocarbonyl)pyrrolidinocarbonyl)-8-(1-adamantylmethyl-N-(methyl)aminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereoisomers)

The compound was prepared essentially as in example 185 except that thecompound of example 220 was used as substrate instead of the compound ofexample 141 in step a. The compound was tested as theN-methyl-D-glucamine salt.

EXAMPLE 224

Preparation ofcis-7-(2S-(1R-carboxyethylaminocarbonylmethyl)pyrrolidinocarbonyl)-8-(1-adamantylmethyl-N-(methyl)aminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

a.cis-7-(2S-(carboxymethyl)pyrrolidinocarbonyl)-8-(1-adamantylmethyl-N-(methyl)aminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The reaction was performed essentially as in example 141 except that thecompound of example 220 step a. was used instead of the compound ofexample 14.

b.cis-7-(2S-(1R-carboxyethylaminocarbonylmethyl)pyrrolidinocarbonyl)-8-(1-adamantylmethyl-N-(methyl)aminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The compound was prepared essentially as in example 185 except that thecompound from step a. above was used as substrate instead of thecompound of example 141 in step a. The compound was tested as theN-methyl-D-glucamine salt.

EXAMPLE 225

Preparation ofcis-7-(2S-(1S-carboxyethylaminocarbonylmethyl)pyrrolidinocarbonyl)-8-(1-adamantylmethyl-N-(methyl)aminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The compound was prepared essentially as in example 184 except that thecompound from example 224 step a. was used as substrate instead of thecompound of example 141 in step a. The compound was tested as theN-methyl-D-glucamine salt.

EXAMPLE 226

Preparation ofcis-7-(2R-(1S-carboxyethylaminocarbonylmethyl)pyrrolidinocarbonyl)-8-(1-adamantylmethyl-N-(methyl)aminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

a.cis-7-(2R-(carboxymethyl)pyrrolidinocarbonyl)-8-(1-adamantylmethyl-N-(methyl)aminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The reaction was performed essentially as in example 142 except that thecompound of example 220 step a. was used instead of the compound ofexample 14.

b.cis-7-(2R-(1S-carboxyethylaminocarbonylmethyl)pyrrolidinocarbonyl)-8-(1-adamantylmethyl-N-(methyl)aminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The compound was prepared essentially as in example 184 except that thecompound from step a. above was used as substrate instead of thecompound of example 141 in step a. The compound was tested as theN-methyl-D-glucamine salt.

EXAMPLE 227

Preparation ofcis-7-(2S-(methoxycarbonylmethylaminocarbonyl)pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The compound was prepared essentially as in example 25 but using themethyl ester L-prolylglycine as substrate instead of L-alanine methylester. Found: C, 62.87; H, 7.47; N, 5.02. C₃₇ H₄₃ N₃ O₅. 1.1 EtOAc and4.5 H₂ O requires C, 63.12; H, 7.78; N, 5.33%

EXAMPLE 228

Preparation ofcis-7-(2S-(1R-carboxyethylaminocarbonyl)pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The compound was prepared essentially as in example 64 but using thebenzyl ester L-prolyl-D-alanine in step a. instead of the dibenzyl esterof aspartic acid. The compound was further characterised and tested asthe N-methyl-D-glucamine salt. Found: C, 60.11; H, 8.22; N, 6.22. C₄₄H₆₀ N₄ O₁₀. 4.4 H₂ O requires C, 59.81; H, 7.84; N, 6.34%

EXAMPLE 229

Preparation ofcis-7-(2R-(carboxymethylaminocarbonyl)-5-oxopyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereomer 1

The compound was prepared essentially as in example 64 but using thebenzyl ester D-pyroglutamyl-glycine in step a. instead of the dibenzylester of aspartic acid. The product of step a. was separated into itsconstituent diastereomers by chromatography (silica 30% ethyl acetateand 70% dichloromethane). The less polar material was hydrogenated togive the compound of this example. The compound was furthercharacterised and tested as the N-methyl-D-glucamine salt. Found: C,54.22; H, 7.26; N, 5.54. C₄₃ H₅₆ N₄ O₁₁. 8.0 H₂ O requires C, 54.42; H,7.60; N, 5.90%

EXAMPLE 230

Preparation ofcis-7-(2R-(carboxymethylaminocarbonyl)-5-oxopyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereomer 2

The compound was prepared essentially as in example 229 except that themore polar material isolated after the chromatography was hydrogenatedto give the compound of this example. The compound was furthercharacterised and tested as the N-methyl-D-glucamine salt. Found: C,54.88; H, 7.20; N, 6.11. C₄₃ H₅₆ N₄ O₁₁ .8.0 H₂ O requires C, 54.42; H,7.60; N, 5.90%

EXAMPLE 231

Preparation ofcis-7-(2R-(1R-carboxyethylaminocarbonylmethyl)pyrrolidinocarbonyl)-8-(1-adamantylmethyl-N-(methyl)aminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The compound was prepared essentially as in example 185 except that thecompound from example 226 step a. was used as substrate instead of thecompound of example 141 in step a.

EXAMPLE 232

Preparation ofcis-7-(2S-(1R-(methoxycarbonyl)ethylaminocarbonylmethyl)-pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (single diastereomer)

The compound was prepared essentially as in example 63 except that thecompound of example 186 was used as substrate instead ofcis-7-(1-S-carboxyl-2-methylpropylaminocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

EXAMPLE 233

Preparation ofcis-7-(2R-(carboxymethylaminocarbonyl)-4-thiopyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane

a.cis-7-(2R-(t-butoxycarboylmethylaminocarbonyl)-4-thiopyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane

This compound was prepared essentially as in example 25 except that2R-(t-butoxycarbonylmethylaminocarbonyl)-4-thiopyrrolidine was used assubstrate instead of L-alanine methyl ester.

b.cis-7-(2-R-(carboxymethylaminocarbonyl)-4-thiopyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane

The compound of step a. above was treated with trifluoroacetic acid togive the title compound of this example.

EXAMPLE 234

Preparation ofcis-7-(2R-(carboxymethylaminocarbonyl)-4-oxothio-pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane

This was prepared from the compound of example 233 step a. by treatmentwith ozone followed by treatment with trifluoroacetic acid.

EXAMPLE 235

Preparation ofcis-7-(2R-(carboxymethylaminocarbonyl)-4-dioxothio-pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane

This was prepared from the compound of example 233 step a. by treatmentwith the tetrabutylammonium salt of oxone followed by treatment withtrifluoroacetic acid.

EXAMPLE 236

Preparation ofcis-7-(2R-(3,5-dicarboxyphenylaminocarbonyl)-pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereomer 1

The compound was prepared essentially as in example 64 but using thedibenzyl ester of D-prolyl-5-aminoisophthalic acid in step a. instead ofthe dibenzyl ester of aspartic acid. The diastereomers were separated atthe benzyl ester stage by column chromatography (silica, 92%dichloromethane and 8% ethyl acetate). The compound with the higherR_(f) was converted to the title compound by hydrogenation. The compoundwas further characterised and tested as the mono-N-methyl-D-glucaminesalt, HPLC; R_(T) =17.4 mins, C8 column, CH₃ CN 50%, 0.1% CH₃ COOH.

EXAMPLE 237

Preparation ofcis-7-(2R-(3,5-dicarboxyphenylaminocarbonyl)-pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereomer 2

The compound was prepared essentially as in example 237 but using thecompound with lower R_(f) after diastereomer separation in the finalhydrogenation step. The compound was further characterised and tested asthe mono-N-methyl-D-glucamine salt, HPLC; R_(T) =9.4 mins, C8 column,CH₃ CN 60%, H₂ O 40%, 0.1% CH₃ COOH.

EXAMPLE 238

Preparation ofcis-7-(2S-(1-R-carboxyethylaminocarbonylethyl)pyrrolidinocarbonyl)-8-(1-adamantylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The compound was prepared essentially as in example 185 but using theproduct of example 215 instead of the compound of example 141. Thecompound was further characterised and tested as theN-methyl-D-glucamine salt, HPLC; R_(T) =21.7 mins, C8 column, CH₃ CN50%, H₂ O 50%, 0.1% CH₃ COOH.

EXAMPLE 239

Preparation ofcis-7-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-phenylethlaminocarbonyl)-8-(1-adamantanemethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereoisomer 1

a. 2,3,5,6-dibenzobicyclo 2.2.2!octane-7,8-dicarboxylic acid anhydride

Anthracene (8.9 g, 0.05 mol) and maleic anhydride (4.9 g, 0.05 mol) wererefluxed for 3 h in toluene (200 ml). Upon cooling the title compoundwas obtained as white crystals which were isolated by filtration (10.2g, 74%).

b. (±)-cis-8-(1-adamantanemethylaminocarbonyl)-2,3,5,6-dibenzo bicyclo2.2.2!octane-7-carboxylic acid

2,3,5,6-dibenzobicyclo(2.2.2.)octane-7,8dicarboxylic acid anhydride(prepared in step a) (276 mg, 1.0 mmol) and 1-adamantanemethylamine (182mg, 1.1 mmol) were dissolved in dry THF (5 ml) and refluxed for 1 h. Athick white precipitate was formed and this was isolated by filtrationand washed with THF to leave the title compound (320 mg, 72%), m.p.237°-9°, found: C, 78.76; H, 7.18; N, 3.33. C₂₉ H₃₁ NO₃ requires C,78.88; H, 7.08; N, 3.17%

c. 3,5-dibenzyloxycarbonyl-nitrobenzene

5-nitro-isophthalic acid (21.1 g, 0.1 mol), thionyl chloride (80 ml) andDMF (10 drops) were stirred and heated for about 1 h until a clearsolution was obtained. Excess thionyl chloride was removed byevaporation and the residual acid chloride was coevaporated withdichloromethane (2×100 ml) to remove the last traces.

Benzyl alcohol (21.6 g, 0.2 mol) and triethylamine (30.03 g, 0.3 mol)were dissolved in dichloromethane (200 ml) and stirred at 0° under anatmosphere of dry nitrogen and a solution of the acid chloride indichloromethane (50 ml) was added dropwise over 20 min. The solution wasstirred and refluxed for 1 h, and the solution was cooled. The organiclayer was washed with water (2×100 ml), saturated sodiumhydrogencarbonate solution (100 ml) and dried over magnesium sulphate.The solution was filtered and evaporated to leave the title compound(39.1 g, 100%).

d. 3,5-dibenzyloxycarbonyl-aniline

The nitro compound prepared in step c above (3.91 g, 10 mol) wasdissolved in ethyl acetate (50 ml) and tin (II) chloride dihydrate(11.27 g, 50 mmol) was added and the mixture stirred and heated at 70°under an atmosphere of nitrogen for 1 h . The mixture was pouredcarefully onto 5% sodium hydrogencarbonate solution (200 ml) and afurther aliquot of ethyl acetate (100 ml) was added. After shaking theorganic layer was separated and the aqueous layer was extracted withmore ethyl acetate (50 ml). The combined organic layers were washed withbrine, and dried, filtered and evaporated to leave a pale yellow solid(3.25 g, 90%).

e.N-tert-butyloxycarbonyl-1S-(3,5-dibenzloxycarbonylphenylaminocarbonyl)-2-phenylethylamine

BOC-L-phenylalanine (8.76 g, 33 mmol) was dissolved in drydichloromethane (200 ml) and dry diisopropylethylamine (11.48 ml, 66mmol) was added followed by PyBROP (15.33 g, 33 mmol). The mixture wasstirred at room temperature for 5 min and then the amine prepared instep d above (7.22 g, 20 mmol) was added. The solution was stirred atroom temperature for a further 5 h and the solution was then washedsequentially with 2M hydrochloric acid, water, saturated sodiumhydrogencarbonate solution and water and finally dried, filtered andevaporated to leave an oil. This was purified by column chromatography(90% dichloromethane and 10% ethyl acetate) to leave the title compoundas a white solid (11.0 g, 90%)

f.cis-7-(1S-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-8-(1-adamantanemethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereoisomer 1

N-tert-butyloxycarbonyl-1S-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-phenylethylamineprepared in step e above (8.0 g, 13 mmol) was dissolved intrifluoroacetic acid (40 ml) and stirred at room temperature for 30 min.The solvent was removed by evaporation and the residue taken up in drydichloromethane (50 ml) and basified with diisopropylethylamine.

Meanwhile (±)-cis-8-(1-adamantanemethylaminocarbonyl)-2,3,5,6-dibenzobicyclo 2.2.2!octane-7-carboxylic acid prepared in step b above (5.75 g,13 mmol) was suspended in dry dichloromethane (150 ml) anddiisopropylethylamine (4.6 ml, 26 mmol) was added followed by PyBOP(6.76 g, 13 mmol). The solution was stirred until a clear solution wasobtained and the solution of amine prepared above was added. Afterstirring at room temperature for 3 h, the solution was washedsequentially with 2M hydrochloric acid and water, dried, filtered andevaporated. The residual oil was purified by column chromatography (90%dichloromethane and 10% ethyl acetate) to leave two compounds. The lesspolar was material was designated the title compound (4.65 g).

g.cis-7-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-8-(1-adamantanemethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereoisomer 1

The dibenzylester prepared in step f above (4.65 g, 5.0 mmol) wasdissolved in 1:1 methanolic THF (40 ml). 10% palladium on charcoal (400mg) was added and the reaction was stirred under an atmosphere ofhydrogen overnight. The catalyst was removed by filtration throughcelite and the product isolated by evaporation (3.53 g).

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt found: C, 61.38; H, 7.54 ; N, 4.24. C₆₀ H₇₉N₅ O₁₇. 4.2 mol dioxan requires C, 60.99; H, 7.51; N, 4.63%

EXAMPLE 240

Preparation ofcis-7-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-8-(1-adamantanemethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereoisomer 2

The compound was prepared essentially as in example 239 except that themore polar material from the chromatography described in step f was usedin the final hydrogenation.

The compound was further characterised and tested as theN-methyl-D-glucamine salt found: C, 64.34; H, 6.64; N, 4.70. C₅₃ H₆₂ N₄O₁₂. 1.7 mol dioxan. 0.8 H₂ O requires C, 64.63; H, 7.00; N, 5.04%

EXAMPLE 241

Preparation ofcis-7-(1R-(3,5-dicarboxyphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-8-(1-adamantanemethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereoisomer 1

The compound was prepared essentially as in example 239 except thatBOC-D-phenylalanine was used in step e instead of BOC-L-phenylalanine.

The compound was further characterised and tested as theN-methyl-D-glucamine salt found: C, 65.66; H, 6.68; N, 5.46. C₅₃ H₆₂ N₄O₁₂. 1.3 H₂ O requires C, 65.55; H, 6.71; N, 5.76%

EXAMPLE 242

Preparation ofcis-7-(1R-(3,5-dicarboxyphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-8-(1-adamantanemethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereoisomer 2

The compound was prepared essentially as in example 241 except that themore polar material from the chromatography described in step f was usedin the final hydrogenation.

The compound was further characterised and tested as theN-methyl-D-glucamine salt found: C, 64.77; H, 7.00; N, 5.90. C₅₃ H₆₂ N₄O₁₂. 2.0 H₂ O requires C, 64.75; H, 6.76; N, 5.69%

EXAMPLE 243

Preparation ofcis-7-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-cyclohexylethylaminocarbonyl)-8-(1-adamantanemethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The compound was prepared essentially as in example 239 except thatBOC-L-2-cyclohexylalanine was used in step e instead ofBOC-L-phenylalanine and no attempt was made to separate thediastereomers in step.

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt found: C, 60.31; H, 8.00; N, 5.84. C₆₀ H₈₅N₅ O₁₇. 2.5 H₂ O requires C, 60.38; H, 7.60; N, 5.86%

EXAMPLE 244

Preparation ofcis-7-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-(2-thiophenyl)-ethylaminocarbonyl)-8-(1-adamantanemethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereoisomer 1

The compound was prepared essentially as in example 239 except thatBOC-L-2-thiophenylalanine was used in step e instead ofBOC-L-phenylalanine.

The compound was further characterised and tested as theN-methyl-D-glucamine salt found: C, 58.61; H, 6.43; N, 5.00. C₅₁ H₆₀ N₄O₁₂ S. 5.0 H₂ O requires C, 58.72; H, 6.76; N, 5.37%

EXAMPLE 245

Preparation ofcis-7-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-thiophenyl)ethylaminocarbonyl)-8-(1-adamantanemethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereoisomer 2

The compound was prepared essentially as in example 244 except that themore polar material from the chromatography described in step f was usedin the final hydrogenation.

The compound was further characterised and tested as theN-methyl-D-glucamine salt found: C, 59.26; H, 6.66; N, 5.00. C₅₁ H₆₀ N₄O₁₂ S. 4.5 H₂ O requires C, 59.23; H, 6.73; N, 5.40%

EXAMPLE 246

Preparation ofcis-7-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-(4-fluorophenyl)-ethylaminocarbonyl)-8-(1-adamantanemethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereoisomer 1

The compound was prepared essentially as in example 239 except thatBOC-L-4-fluorophenylalanine was used in step e instead ofBOC-L-phenylalanine.

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt found: C, 59.38; H, 7.19; N, 5.92. C₆₀ H₇₈N₅ O₁₇ F. 3.1 H₂ O requires C, 59.24; H, 6.98; N, 5.76%

EXAMPLE 247

Preparation ofcis-7-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-(4-fluorophenyl)ethylaminocarbonyl)-8-(1-adamantanemethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereoisomer 2

The compound was prepared essentially as in example 246 except that themore polar material from the chromatography described in step f was usedin the final hydrogenation.

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt found: C, 60.18; H, 7.21; N, 6.01. C₆₀ H₇₈N₅ O₁₇ F. 2.3 H₂ O requires C, 59.94; H, 6.93; N, 5.83%

EXAMPLE 248

Preparation ofcis-7-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-(4-chlorophenyl)-ethylaminocarbonyl)-8-(1-adamantanemethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereoisomer 1

The compound was prepared essentially as in example 239 except thatBOC-L-4-chlorophenylalanine was used in step e instead ofBOC-L-phenylalanine.

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt found: C, 59.16; H, 7.04; N, 5.72. C₆₀ H₇₈N₅ O₁₇ Cl. 1.9 H₂ O requires C, 59.49; H, 6.81; N, 5.78%

EXAMPLE 249

Preparation ofcis-7-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-(4-chlorophenyl)ethylaminocarbonyl)-8-(1-adamantanemethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereoisomer 2

The compound was prepared essentially as in example 248 except that themore polar material from the chromatography described in step f was usedin the final hydrogenation.

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt found: C, 59.08; H, 6.97; N, 5.43. C₆₀ H₇₈N₅ O₁₇ Cl. 2.7 H₂ O requires C, 58.85; H, 6.86; N, 5.72%

EXAMPLE 250

Preparation ofcis-7-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-(4-methoxyphenyl)-ethylaminocarbonyl)-8-(1-adamantanemethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereoisomer 1

The compound was prepared essentially as in example 239 except thatBOC-L-4-methoxyphenylalanine was used in step e instead ofBOC-L-phenylalanine.

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt found: C, 59.36; H, 7.28; N, 5.77. C₆₁ H₈₁N₅ O₁₈. 3.3 H₂ O requires C, 59.45; H, 7.17; N, 5.68%

EXAMPLE 251

Preparation ofcis-7-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-(4-methoxyphenyl)ethylaminocarbonyl)-8-(1-adamantanemethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereoisomer 2

The compound was prepared essentially as in example 250 except that themore polar material from the chromatography described in step f was usedin the final hydrogenation.

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt found: C, 57.14; H, 7.26; N, 5.32. C₆₁ H₈₁N₅ O₁₈. 6.3 H₂ O requires C, 57.01; H, 7.34; N, 5.45%

EXAMPLE 252

Preparation ofcis-7-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-(2-naphthyl)-ethylaminocarbonyl)-8-(1-adamantanemethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereoisomer 1

The compound was prepared essentially as in example 239 except thatBOC-L-3-(2-naphthyl)alanine was used in step e instead ofBOC-L-phenylalanine.

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt found: C, 61.14 H, 7.03; N, 5.64. C₆₄ H₈₁N₅ O₁₇. 3.5 H₂ O requires C, 61.20; H, 7.07; N, 5.58%

EXAMPLE 253

Preparation ofcis-7-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-(2-naphthyl)ethylaminocarbonyl)-8-(1-adamantanemethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereoisomer 2

The compound was prepared essentially as in example 252 except that themore polar material from the chromatography described in step f was usedin the final hydrogenation.

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt found: C, 61.59; H, 7.11; N, 5.52. C₆₄ H₈₁N₅ O₁₇. 4.2 H₂ O requires C, 61.59; H, 7.11; N, 5.52%

EXAMPLE 254

Preparation ofcis-7-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-(2-fluorophenyl)-ethylaminocarbonyl)-8-(1-adamantanemethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereoisomer 1

The compound was prepared essentially as in example 239 except thatBOC-L-2-fluorophenylalanine was used in step e instead ofBOC-L-phenylalanine.

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt found: C, 58.63; H, 6.99; N, 5.49. C₆₀ H₇₈N₅ O₁₇ F. 4.0 H₂ O requires C, 58.44; H, 7.04; N, 5.68%

EXAMPLE 255

Preparation ofcis-7-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-(2-fluorophenyl)ethylaminocarbonyl)-8-(1-adamantanemethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereoisomer 2

The compound was prepared essentially as in example 254 except that themore polar material from the chromatography described in step f was usedin the final hydrogenation.

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt found: C, 58.49; H, 7.00; N, 5.67. C₆₀ N₇₈N₅ O₁₇ F. 4.2 H₂ O requires C, 58.34; H, 7.04; N, 5.67%

EXAMPLE 256

Preparation ofcis-7-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-(3-fluorophenyl)-ethylaminocarbonyl)-8-(1-adamantanemethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereoisomer 1

The compound was prepared essentially as in example 239 except thatBOC-L-3-fluorophenylalanine was used in step e instead ofBOC-L-phenylalanine.

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt found: C, 58.60; H, 7.04; N, 5.62. C₆₀ H₇₈N₅ O₁₇ F. 3.9 H₂ O requires C, 58.55; H, 7.038; N, 5.69%

EXAMPLE 257

Preparation ofcis-7-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-(3-fluorophenyl)ethylaminocarbonyl)-8-(1-adamantanemethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereoisomer 2

The compound was prepared essentially as in example 256 except that themore polar material from the chromatography described in step f was usedin the final hydrogenation.

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt found: C, 58.49; H, 7.09; N, 5.69%

EXAMPLE 258

Preparation ofcis-7-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-(2-chlorophenyl)-ethylaminocarbonyl)-8-(1-adamantanemethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The compound was prepared essentially as in example 239 except thatBOC-L-2-chlorophenylalanine was used in step e instead ofBOC-L-phenylalanine and no attempt was made to separate thediastereomers in step f.

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt found: C, 57.69; H, 7.05; N, 5.55. C₆₀ H₇₈N₅ O₁₇ Cl. 4.1 H₂ O requires C, 57.59; H, 6.95; N, 5.55%

EXAMPLE 259

Preparation ofcis-7-(1R-(3,5-dicarboxyphenylaminocarbonyl)-2-(2-thiophenyl)ethylaminocarbonyl)-8-(1-adamantanemethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereoisomer 2

The compound was prepared essentially as in example 245 except thatexcept that BOC-D-2-thiophenylalanine was used in step e instead ofBOC-L-phenylalanine.

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt

EXAMPLE 260

Preparation ofcis-7-(1S-(phenylaminocarbonyl)-2-phenyl-ethylaminocarbonyl)-8-(1-adamantanemethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereoisomer 1

The compound was prepared essentially as in example 239 step f exceptthat N-tert-butyloxycarbonyl-1S-(phenylaminocarbonyl)-2-phenylethylaminewas used instead ofN-tert-butyloxycarbonyl-1S-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-phenylethylamine.As before, the less polar compound after chromatography was designatedthe compound of this example. found: C, 78.33; H, 6.94; N, 6.05 C₄₄ H₄₅N₃ O₃. 0.4 ethyl acetate requires C, 78.49; H, 6.94; N, 6.05%

EXAMPLE 261

Preparation ofcis-7-(1S-(phenylaminocarbonyl)-2-phenylethylaminocarbonyl)-8-(1-adamantanemethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereoisomer 2

The compound was prepared essentially as in example 260 except that themore polar material from the chromatography was designated as thecompound of this example found: C, 79.37; H, 6.96; N, 6.24 C₄₄ H₄₅ N₃ O₃requires C, 79.61; H, 6.83; N, 6.33%

EXAMPLE 262

Preparation ofcis-7-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-(4-hydroxyphenyl)-ethylaminocarbonyl)-8-(1-adamantanemethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereoisomer 2

The compound was prepared essentially as in example 239 except thatBOC-L-tyrosine was used in step e instead of BOC-L-phenylalanine.

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt

EXAMPLE 263

Preparation ofcis-7-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-(4-hydroxyphenyl)ethylaminocarbonyl)-8-(1-adamantanemethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereoisomer 2

The compound was prepared essentially as in example 262 except that themore polar material from the chromatography described in step f was usedin the final hydrogenation.

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt found: C, 57.11; H, 7.46; N, 5.79. C₆₀ H₇₉N₅ O₁₈. 6.0 H₂ O requires C, 56.95; H, 7.24; N, 5.53%

EXAMPLE 264

Preparation ofcis-7-(1R-(3.5-dicarboxyphenylaminocarbonyl)-2-(4-hydroxyphenyl)-ethylaminocarbonyl)-8-(1-adamantanemethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereoisomer 1

The compound was prepared essentially as in example 239 except thatBOC-D-tyrosine was used in step e instead of BOC-L-phenylalanine.

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt found: C, 57.05; H, 7.09; N, 5.23. C₆₀ H₇₉N₅ O₁₈. 6.1 H₂ O requires C, 56.79; H, 7.25; N, 5.52%

EXAMPLE 265

Preparation ofcis-7-(1R-(3,5-dicarboxyphenylaminocarbonyl)-2-(4-hydroxyphenyl)ethylaminocarbonyl)-8-(1-adamantanemethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereoisomer 2

The compound was prepared essentially as in example 26 except that themore polar material from the chromatography described in step f was usedin the final hydrogenation.

EXAMPLE 266

Preparation ofcis-7-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-8-(1-cycloheptanemethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereoisomer 1

The compound was prepared essentially as in example 239 except thatcycloheptanemethylamine was used in step b instead of1-adamantanemethylamine.

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt found: C, 59.25; H, 7.17; N, 5.94. C₅₇ H₇₇N₅ O₁₇. 2.9 H₂ O requires C, 59.14; H, 7.22; N, 6.06%

EXAMPLE 267

Preparation ofcis-7-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-8-(cycloheptanemethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereoisomer 2

The compound was prepared essentially as in example 266 except that themore polar material from the chromatography described in step f was usedin the final hydrogenation.

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt found: C, 59.14; H, 7.15; N, 6.10. C₅₇ H₇₇N₅ O₁₇. 2.9 H₂ O requires C, 59.14; H, 7.22; N, 6.06%

EXAMPLE 268

Preparation ofcis-7-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-8-(1-cyclohexanemethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereoisomer 1

The compound was prepared essentially as in example 239 except thatcyclohexanemethylamine was used in step b instead of1-adamantanemethylamine.

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt found: C, 58.75; H, 7.11; N, 5.85. C₅₆ H₇₅N₅ O₁₇. 3.2 H₂ O requires C, 58.58; H, 7.15; N, 6.06%

EXAMPLE 269

Preparation ofcis-7-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-8-(cyclohexanemethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereoisomer 2

The compound was prepared essentially as in example 268 except that themore polar material from the chromatography described in step f was usedin the final hydrogenation.

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt found: C, 58.61; H, 7.19; N, 6.18. C₅₆ H₇₅N₅ O₁₇. 3.1 H₂ O requires C, 58.69; H, 7.14; N, 6.11%

EXAMPLE 270

Preparation ofcis-7-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-8-(1-naphthalenemethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereoisomer 1

The compound was prepared essentially as in example 239 except that1-naphthalenemethylamine was used in step b instead of1-adamantanemethylamine.

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt found: C, 59.82; H, 6.70; N, 6.04. C₆₀ H₇₁N₅ O₁₇. 3.7 H₂ O requires C, 60.03; H, 6.58; N, 5.83%

EXAMPLE 271

Preparation ofcis-7-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-8-(1-naphthalenemethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereoisomer 2

The compound was prepared essentially as in example 270 except that themore polar material from the chromatography described in step f was usedin the final hydrogenation.

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt found: C, 58.02; H, 6.84; N, 5.96. C₆₀ H₇₁N₅ O₁₇. 5.6 H₂ O requires C, 58.31; H, 6.71; N, 5.67%

EXAMPLE 272

Preparation ofcis-7-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-8-(3,4-dichlorophenylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereoisomer 1

The compound was prepared essentially as in example 239 except that3,4-dichlorobenzylamine was used in step b instead of1-adamantanemethylamine.

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt found: C, 56.58; H, 6.27; N, 5.90. C₅₆ H₆₇Cl₂ N₅ O₁₇. 1.9H₂ O requires C, 56.65; H, 6.01; N, 5.89%

EXAMPLE 273

Preparation ofcis-7-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-8-(3,4-dichlorophenylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereoisomer 2

The compound was prepared essentially as in example 272 except that themore polar material from the chromatography described in step f was usedin the final hydrogenation.

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt found: C, 56.98; H, 6.04; N, 6.05. C₅₆ H₆₇Cl₂ N₅ O₁₇. 1.4 H₂ O requires C, 57.08; H, 5.97; N, 5.94%

EXAMPLE 274

Preparation ofcis-7-(1S-(3,5-dicarboxyphenylaminocarbonyl)-3-phenylpropylaminocarbonyl)-8-(1-adamantanemethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The compound was prepared essentially as in example 239 except that2S-(tert-butyloxycarbonylamino)-4-phenylbutanoic acid was used in step einstead of BOC-L-phenylalanine and no attempt was made to separate thediastereomers in step f.

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt found: C, 59.76; H, 7.03; N, 5.79. C₆₁ H₈₁N₅ O₁₇. 3.6 H₂ O requires C, 60.01; H, 7.28; N, 5.74%

EXAMPLE 275

Preparation ofcis-7-(1R-(3,5-dicarboxyphenylaminocarbonyl)-3-phenylpropylaminocarbonyl)-8-(1adamantanemethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The compound was prepared essentially as in example 239 except that2R-(tert-butyloxycarbonylamino)-4-phenylbutanoic acid was used in step einstead of BOC-L-phenylalanine and no attempt was made to separate thediastereomers in step f.

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt found: C, 59.65; H, 7.01; N, 5.51. C₆₁ H₈₁N₅ O₁₇. 3.7 H₂ O requires C, 59.93; H, 7.28; N, 5.73%

EXAMPLE 276

preparation ofcis-7-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-phenylethyl-N(methyl)-aminocarbonyl)-8-(1-adamantanemethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The compound was prepared essentially as in example 239 except thatN-methyl-BOC-L-phenylalanine was used in step e instead ofBOC-L-phenylalanine and no attempt was made to separate thediastereomers in step f.

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt found: C, 58.78; H, 7.09; N, 5.70. C₆₁ H₈₁N₅ O₁₇. 4.7 H₂ O requires C, 59.04; H, 7.34; N, 5.64%

EXAMPLE 277

Preparation ofcis-7-(1S-(3,5-dicarboxyphenylaminocarbonyl)-3-phenylmethylaminocarbonyl)-8-(1-adamantanemethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The compound was prepared essentially as in example 239 except thatBOC-L-phenylglycine was used in step e instead of BOC-L-phenylalanineand no attempt was made to separate the diastereomers in step f.

The compound was further characterised and tested as theN-methyl-D-glucamine salt found: C, 64.20; H, 6.75; N, 5.80. C₅₂ H₆₀ N₄O₁₂. 2.2 H₂ O requires C, 64.21; H, 6.67; N, 5.76%

EXAMPLE 278

Preparation ofcis-7-(1S-(3-carboxyphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-8-(1-adamantanemethylaminocarbonyl)-2,3,5,6,-dibenzobicyclo2.2.2!octane Diastereoisomer 1

The compound was prepared essentially as in example 239 steps f and gexcept thatN-tert-butyloxycarbonyl-1S-(3-benzyloxycarbonylphenylaminocarbonyl)-2-phenylethylaminewas used instead ofN-tert-butyloxycarbonyl-1S-(3,5-dibenzyloxycarbonyl-phenylaminocarbonyl)-2-phenylethylamine in step f. As before, the less polarcompound after chromatography in step f was taken through to thecompound of this example.

The compound was further characterised and tested as theN-methyl-D-glucamine salt found: C, 69.70; H, 7.00; N, 5.96. C₅₂ H₆₂ N₄O₁₀. 0.7 H₂ O requires C, 69.45; H, 7.10; N, 6.23%

EXAMPLE 279

Preparation ofcis-7-(1S-(3-carboxyphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-8-(1-adamantanemethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereoisomer 2

The compound was prepared essentially as in example 278 except that themore polar.

The compound was further characterised and tested as theN-methyl-D-glucamine salt found: C, 66.60; H, 7.21; N, 6.06. C₅₂ H₆₂ N₄O₁₀. 1.9 H₂ O requires C, 66.57; H, 7.08; N, 5.97%

EXAMPLE 280

Preparation ofcis-7-(1S-(3-carboxy-5-methoxycarbonylphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-8-(1-adamantanemethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The compound was prepared essentially as in example 239 expect that3-methoxycarbonyl-5-nitrobenzoic acid was used in step c instead of5-nitro-isophthalic acid.

The compound was further characterised and tested as theN-methyl-D-glucamine salt found: C, 65.81; H, 6.93; N, 5.79. C₅₄ H₆₄ N₄O₁₂. 1.5 H₂ O requires C, 65.70; H, 6.83; N, 5.67%

EXAMPLE 281

Preparation ofcis-7-(1S-(3,4-dicarboxyphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-8-(1-adamantanemethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The compound was prepared essentially as in example 239 except that4-nitrophthalic acid was used in step c instead of 5-nitroisophthalicacid.

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt found: C, 60.31; H, 7.22; N, 5.76. C₆₀ H₇₉N₅ O₁₇. 1.5 H₂ O requires C, 60.29; H, 7.16; N, 5.86%

EXAMPLE 282

Preparation ofcis-7-(1S-(3,5-ditetrazolylphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-8-(1-adamantanemethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The compound was prepared essentially as in example 239 except that thebis pivaloyloxymethyl (POM) derivative ofN-tert-butyloxycarbonyl-1S-(3,5-ditetrazolylphenylaminocarbonyl)-2-phenylethylaminewas used instead ofN-tert-butyloxycarbonyl-1S-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-phenylethylaminein step f and the deprotection in step g was performed with methanolicammonia solution.

EXAMPLE 283

Preparation ofcis-7-(1S-(2-carboxyphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-8-(1-adamantanemethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The compound was prepared essentially as in example 239 steps f and gexcept thatN-tert-butyloxycarbonyl-1S-(2-benzyloxycarbonylphenylaminocarbonyl)-2-phenylethylaminewas used instead ofN-tert-butyloxycarbonyl-1S-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-phenylethylaminein step f. No attempt was made to separate diastereoisomers.

The compound was further characterised and tested as theN-methyl-D-glucamine salt found: C, 63.51; H, 7.00; N, 5.52, C₅₂ H₆₂ N₄O₁₀. 4.2 H₂ O requires C, 63.77; H, 7.25; N, 5.72%.

EXAMPLE 284

Preparation ofcis-7-(1S-(4-carboxyphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-8-(1-adamantanemethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereomer 1

The compound was prepared essentially as in example 239 steps f and gexcept thatN-tert-butyloxycarbonyl-1S-(2-benzyloxycarbonylphenylaminocarbonyl)-2-phenylethylaminewas used instead ofN-tert-butyloxycarbonyl-1S-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-phenylethylaminein step f. The less polar material described from the chromatography instep f was taken through to the title compound of this example.

The compound was further characterised and tested as theN-methyl-D-glucamine salt found: C, 66.60; H, 7.21; N, 6.06. C₅₂ H₆₂ N₄O₁₀. 1.9 H₂ O requires C, 66.57; H, 7.08; N, 5.97%.

EXAMPLE 285

Preparation ofcis-7-(1S-(4-carboxyphenylaminocarbonyl)-2-phenylaminocarbonyl-8-(1-adamantanemethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereomer 2

The more polar diastereomer described in example 284 was taken throughas the title compound of this example.

The compound was further characterised and tested as theN-methyl-D-glucamine salt found: C, 62.98; H, 7.26; N, 6.02. C₅₂ H₆₂ N₄O₁₀ 4.6 H₂ O requires C, 63.32; H, 7.28; N, 5.68%. H₂ O requires C,63.32; H, 7.28; N, 5.68%.

EXAMPLE 286

Preparation ofcis-7-(1S-(3,5-dimethoxycarbonylphenylaminocarbonyl)-2-phenylethylamino-carbonyl-8-(1-adamantanemethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereomer 1

The compound of example 239 was treated with an excess of diazomethaneto leave the title compound after quenching and evaporation found: C,74.00; H, 6.40; N, 5.32. C₄₈ H₄₉ N₃ O₇ requires C, 73.92; H, 6.33; N,5.39%

EXAMPLE 287

Preparation ofcis-7-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-8-(1-(1-adamantane)-1-methylethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The compound was prepared essentially as in example 239 except that1-(1-adamantane)-1-methylethylamine was used in step b instead of1-adamantanemethylamine and no attempt was made to separate thediastereomers described in step f. m.p 195-°8°.

The compound was further characterised and tested as the diN-methyl-D-glucamine salt found: C, 58.96; H, 7.33; N, 5.59. C₆₂ H₈₃ N₅O₁₇. 5 H₂ O requires C, 659.08; H, 7.43; N, 5.56%

EXAMPLE 288

Preparation ofcis-7-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-8-(3-indolylethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereoisomer 1

The compound was prepared essentially as in example 239 except that3-indolylethylamine was used in step b instead of1-adamantanemethylamine.

The compound was further characterised and tested as the diN-methyl-D-glucamine salt found: C, 58.37; H, 6.44; N, 7.04. C₅₉ H₇₂ N₆O₁₇. 4 H₂ O requires C, 58.60; H, 6.67; N, 5.95%

EXAMPLE 289

Preparation ofcis-7-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-8-(3-indolylethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereoisomer 2

The compound was prepared essentially as in example 288 except that themore polar material from the chromatography described in step f was usedin the final hydrogenation.

The compound was further characterised and tested as the diN-methyl-D-glucamine salt found: C, 59.83; H, 6.20; N, 6.76. C₅₉ H₇₂ N₆O₁₇. 2.4 H₂ O requires C, 60.03; H, 6.56; N, 7.12%

EXAMPLE 290

Preparation ofcis-7-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-8-(2-thiophenylmethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The compound was prepared essentially as in example 239 except that2-thiophenylmethylethylamine was used in step b instead of1-adamantanemethylamine and no attempt was made to separate thediastereomers described in step f.

The compound was further characterised and tested as the diN-methyl-D-glucamine salt found: C, 52.68; H, 6.43; N, 5.67. C₅₄ H₆₇ N₆O₁₇ S. 7.4 H₂ O requires C, 52.99; H, 6.74; N, 5.72%

EXAMPLE 291

Preparation ofcis-7-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-8-(2-phenylethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The compound was prepared essentially as in example 239 except that2-phenylethylamine was used in step b instead of 1-adamantanemethylamineand no attempt was made to separate the diastereomers described in stepf.

The compound was further characterised and tested as the diN-methyl-D-glucamine salt found: C, 59.15; H, 6.83; N, 5.81. C₅₇ H₇₁ N₅O₁₇. 3.5 H₂ O requires C, 58.95; H, 6.77; N, 6.03%

EXAMPLE 292

Preparation ofcis-7-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-8-(2-phenylpropylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane (mixture of diastereomers)

The compound was prepared essentially as in example 239 except that3-phenylpropylamine was used in step b instead of1-adamantanemethylamine and no attempt was made to separate thediastereomers described in step f.

The compound was further characterised and tested as the diN-methyl-D-glucamine salt found: C, 59.39; H, 6.79; N, 5.90. C₅₈ H₇₃ N₅O₁₇. 3.8 H₂ O requires C, 59.38; H, 6.85; N, 5.96%

EXAMPLE 293

Preparation ofcis-7-(1S-(3-carboxyphenylaminocarbonyl)-2-(2-thiophenyl)ethylaminocarbonyl)-8-(1-adamantanemethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereomer 1

The compound was prepared essentially as in example 239 except that stepe was carried out using BOC-L-3-(2-thiophenyl)alanine instead ofBOC-L-phenylalanine and 3-benzyloxycarbonylaniline instead of3,5-dibenzyloxycarbonylaniline. The product of this reaction was used instep f instead ofN-tert-butyloxycarbonyl-1S-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-phenylethylamine.

The compound was further characterised and tested as theN-methyl-D-glucamine salt found: C, 66.21; H, 6.62; N, 5.87. C₅₀ H₆₀ N₄O₁₀ S requires C, 66.06; H, 6.65; N, 6.16%

EXAMPLE 294

Preparation ofcis-7-(1S-(3-carboxyphenylaminocarbonyl)-2-(2-thiophenyl)ethylaminocarbonyl)-8-(1-adamantanemethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2.!octane Diastereomer 2

The compound was prepared essentially as in example 293 except that themore polar material from the chromatography described in step f was usedin the final hydrogenation.

The compound was further characterised and tested as theN-methyl-D-glucamine salt found: C, 66.32; H, 6.81; N, 5.88. C₅₀ H₆₀ N₄O₁₀ S requires C, 66.06; H, 6.65; N, 6.16%

EXAMPLE 295

Preparation ofcis-7-(1S-(3-carboxyphenylaminocarbonyl)-2-(2-thiophenyl)ethylaminocarbonyl)-8-(1-naphthalenemethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereomer 1

The compound was prepared essentially as in example 293 except that1-naphthalenemethylamine was used in step b instead of1-adamantanemethylamine.

The compound was further characterised and tested as theN-methyl-D-glucamine salt found: C, 58.71; H, 6.21; N, 5.85. C₅₀ H₅₂ N₄O₁₀ S. 6.4 H₂ O requires C, 59.06; H, 6.43; N, 5.51%

EXAMPLE 296

Preparation ofcis-7-(1S-(3-carboxyphenylaminocarbonyl)-2-(2-thiophenyl)ethylaminocarbonyl)-8-(1-naphthalenemethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereomer 2

The compound was prepared essentially as in example 295 except that themore polar material from the chromatography described in step f was usedin the final hydrogenation. f was used in the final hydrogenation.

The compound was tested as the N-methyl-D-glucamine salt.

EXAMPLE 297

Preparation ofcis-7-(1S-(3-carboxyphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-8-(1-naphthalenemethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereomer 1

The compound was prepared essentially as in example 295 except thatBOC-L-phenylalanine was used in step e instead ofBOC-L-3-(2-thiophenyl)alanine.

The compound was further characterised and tested as theN-methyl-D-glucamine salt found: C, 58.71; H, 6.21; N, 5.85. C₅₀ H₅₂ N₄O₁₀ S. 6.4 H₂ O requires C, 59.06; H, 6.43; N, 5.51%

EXAMPLE 298

Preparation ofcis-7-(1S-(3-carboxyphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-8-(1-naphthalenemethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereomer 2

The compound was prepared essentially as in example 297 except that themore polar material from the chromatography described in step f was usedin the final hydrogenation.

The compound was tested as the N-methyl-D-glucamine salt.

EXAMPLE 299

Preparation ofcis-7-(1S-(3,5-discarboxyphenyl-methylaminocarbonyl)-2-phenylethylaminocarbonyl)-8-(1-adamantanemethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereoisomer 1

The compound was prepared essentially as in example 239 except that3,5-dibenzyloxycarbonylbenzylamine was used in step e instead of3,5-dibenzyloxycarbonylaniline.

The compound was further characterised and tested as theN-methyl-D-glucamine salt found: C, 64.72; H, 6.96; N, 5.88. C₅₄ H₆₄ N₄O₁₂. 2 H₂ O requires C, 64.99; H, 6.88; N, 5.61%

EXAMPLE 300

Preparation ofcis-7-(1S-(3,5-dicarboxyphenylmethylaminocarbonyl)-2-phenylethylaminocarbonyl)-8-(1-adamantanemethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereoisomer 2

The compound was prepared essentially as in example 299 except that themore polar material from the chromatography described in step f was usedin the final hydrogenation.

The compound was further characterised and tested as theN-methyl-D-glucamine salt found: C, 64.99; H, 6.95; N, 5.65. C₅₄ H₆₄ N₄O₁₂. 2 H₂ O requires C, 64.99; H, 6.88; N, 5.61%

EXAMPLE 301

Preparation ofcis-7-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-8-(2-napthalenemethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereoisomer 1

The compound was prepared essentially as in example 239 except that2-naphthalenemethylamine was used in step b instead of1-adamantanemethylamine, found: C, 73.99; H, 5.26; N, 5.41. C₄₆ H₃₇ N₃O₇. requires C, 74.28; H, 5.01; N, 5.65%

The compound was tested as the di N-methyl-D-glucamine salt.

EXAMPLE 302

Preparation ofcis-7-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-8-(2-naphthalenemethylaminocarbonyl)-2,3,5,6-dibenzobicyclo2.2.2!octane Diastereoisomer 2

The compound was prepared essentially as in example 301 except that themore polar material from the chromatography described in step f was usedin the final hydrogenation found: C, 72.76; H, 5.18; N, 5.42. C₄₆ H₃₇ N₃O₇. 1.1 H₂ O requires C, 72.30; H, 5.18; N, 5.50%

The compound was tested as the di N-methyl-D-glucamine salt.

The following ¹ H NMR data were obtained for the compounds described inthe Examples:

Ex.1a. (d⁶ -DMSO) δ7.5 (2H, m), 7.3 (2H, m), 7.2 (4H, m), 4.8 (2H, s),3.6 (2H, s).

Ex.1b. (d⁶ -DMSO) δ11.6 (1H, br s), 7.9 (1H, t), 7.4-6.9 (13H, m), 4.5(1H, s), 4.4 (1H, s), 3.1 (1H, d), 2.9 (2H, m), 2.8 (1H, d), 2.5 (2H,t), 1.6 (2H, m).

Ex.2 (d⁶ -DMSO) δ11.6 (1H, br s), 10.8 (1H, s), 8.0 (1H, t), 7.6-6.8(13H, m), 4.5 (1H, s), 4.3 (1H, d), 3.3-3.0 (3H, d), 2.2-2.4 (3H, m).

Ex.3 (d⁶ -DMSO) δ8.4 (1H, br s), 8.4 (1H, t), 7.4-6.8 (13H, m), 4.4 (2H,d), 4.1 (2H, m), 3.2 (1H, d), 2.8 (1H, d).

Ex.4 (d⁶ -DMSO) δ8.4 (1H, t), 8.0-6.9 (15H, m), 4.7 (1H, dd), 4.5 (1H,dd), 4.5 and 4.3 (2H, 2xs), 3.3 (1H, d), 2.8 (1H, d).

Ex.5 (d⁶ -DMSO) δ8.5 (1H, t), 8.0-6.9 (15H, m), 4.5 (2H, d), 4.3 (2H,m), 3.2 (1H, d), 2.8 (1H, d).

Ex.6 (d⁶ -DMSO) δ11.6 (1H, br s), 7.8 (1H, m), 7.4-6.9 (8H, m), 4.5 (1H,s), 4.4 (1H, s), 3.2-2.6 (4H, m), 2.2-0.9 (11H, m).

Ex.7 (d⁶ -DMSO) δ11.6 (1H, br s), 7.8 (1H, m), 7.4-6.9 (8H, m), 4.5 (1H,s), 4.4 (1H, s), 3.2 (1H, dd), 3.0-2.8 (2H, m), 2.8 (1H, dd) 1.2 (8H,m), 0.9 (3H, t).

Ex.8 (d⁶ -DMSO) δ11.6 (1H, br s), 7.8 (1H, t), 7.4-6.9 (8H, m), 4.5 (1H,d), 4.4 (1H, d), 3.1 (1H, dd), 3.0-2.8 (2H, m), 2.7 (1H, dd) 1.3 (12H,m), 0.9 (3H, t).

Ex.9 (d⁶ -DMSO) δ11.6 (1H, br s), 7.8 (1H, t), 7.4-6.9 (8H, m), 4.5 (1H,d), 4.4 (1H, d), 3.1 (1H, dd), 2.8-2.6 (3H, m), 1.8-0.7 (11H, m).

Ex.10 (d⁶ -DMSO) δ12.6 (1H, br s), 7.7 (1H, t), 7.4-6.9 (8H, m), 4.5(1H, d), 4.4 (1H, d), 3.0 (1H, dd), 2.9 (2H, m), 2.8 (1H, dd), 1.3 (2H,m), 0.9 (9H, s).

Ex.11 (d⁶ -DMSO) δ7.3 (3H, m), 7.2 (1H, m), 7.1 (5H, m), 4.5 (1H, d),4.4 (1H, d), 3.1 (1H, dd), 2.7 (1H, dd), 1.9 (3H, s), 1.8 (6H, m), 1.6(6H, m).

Ex.12 (d⁶ -DMSO) δ7.6 (1H, t), 7.4-6.9 (8H, m), 4.5 (1H, d), 4.4 (1H,d), 3.0 (1H, dd), 2.9 (2H, m), 2.8 (1H, dd), 1.9 (3H, s), 1.6 (6H, m),1.4 (6H, m), 1.1 (2H, t).

Ex.13 (d⁶ -DMSO) δ12.2 (1H br s), 7.4-7.0 (8H, m), 4.6 (1H, dd), 3.4(1H, d), 3.3 (1H, d), 3.1 (1H, d), 1.9 (3H, s), 1.6 (6H, m), 1.4 (6H,m).

Ex.14 (d⁷ -DMF) δ7.7 (1H, t), 7.4 (3H, m), 7.2 (3H, m), 7.1 (2H, m), 4.7(1H, d), 4.6 (1H, d), 3.5 (1H, dd), 3.0 (1H, dd), 2.9 (1H, dd), 2.7 (1H,dd), 2.0 (3H, s), 1.7 (6H, m), 1.5 (6H, s).

Ex.15 (d⁶ -DMSO) δ7.9 (1H, t), 7.0-7.4 (8H, m), 6.6 (1H, t), 4.5 (2H,d), 3.8-3.5 (2H, 2×dd), 3.6 (3H, s), 3.2 (1H, d), 3.0 (1H, dd), 2.5 (1H,dd), 1.9 (3H, b s), 1.2-1.7 (12H, m).

Ex.16a (d⁶ DMSO) δ8.0 (1H, m), 7.4-7.0 (13, m), 6.6 (1H, m), 5.1 (2H,s), 4.4 (2H, s), 3.8 (1H, dd), 3.6 (1H, dd), 3.1 (1H, m), 3.0 (1H, d),2.5 (2H, m), 1.9 (3H, s), 1.6 (6H, q), 1.3 (6H, d).

Ex.16b (d⁶ -DMSO) δ7.8 (1H, m), 7.3-7.0 (8H, m), 6.6 (1H, m), 4.5 (2H,s), 3.7 (1H, dd), 3.4 (1H, m), 3.1 (1H, d), 2.9 (1H, d), 2.5 (2H, m),1.9 (3H, s), 1.6 (6H, q), 1.2 (6H, d).

Ex.17 (CDCl₃) δ7.6 (1H, d), 7.1-7.4 (7H, m), 4.9 (1H, t), 4.6 (1H, d),4.5 (1H, d), 3.6 (3H, s), 3.3 (1H, dd), 3.2 (1H, dd), 2.9 (1H, m), 2.6(1H, m), 2.0 (3H, s), 1.6 (6H, m), 1.3 (6H, s).

Ex.18a (CDCl₃) δ7.6-7.1 (8H, m), 6.0 (1H, d), 5.9 (1H, d), 4.0 (1H, dd),3.8 (1H, dd).

Ex.18b (CDCl₃) δ7.8-6.9 (15H, m), 4.9 (2H, d), 4.6 (1H, d), 4.4 (1H, d),4.0 (1H, dd),3.8 (1H, dd).

Ex.18c (d⁶ -DMSO) δ9.0 (1H, bs), 7.9-7.0 (15H, m), 5.4 (1H, s), 4.6 (2H,d), 4.4 (1H, m), 4.3 (1H, m), 3.1 (1H, m), 2.9 (1H, m).

Ex.19 (d⁶ -DMSO) δ8.9 (1H, bs), 7.4-6.8 (13H, m), 4.6 (2H, s), 4.3 (1H,dd), 4.1 (1H, dd), 3.5 (1H, m), 3.0 (1H, dd), 2.8 (1H, dd).

Ex.20a (CDCl₃) δ7.6-7.1 (8H, m), 5.0 (1H, d), 4.9 (1H, d), 4.2 (1H, dd),4.1 (1H, dd)

Ex.20b (d⁶ -DMSO) δ8.2 (1H, bs), 7.9-6.9 (15H, m), 4.7 and 4.5 (2H,2×s), 4.2 (1H, d), 4.1 (1H, d), 3.1 (2H, m).

Ex.21 (d⁶ -DMSO) δ10.8 (1H, s), 8.0 (1H, bs), 7.5-6.8 (13H, m), 4.7 and4.4 (2H, 2×s), 3.2-2.9 (6H, m).

Ex.22 (d⁶ -DMSO) δ7.7 (1H, bs), 7.4-6.9 (8H, m), 4.7 and 4.4 (2H, 2×s),3.1 (2H, m), 2.7 (1H, dd), 2.3 (1H, d), 1.8 (3H, s), 1.6 (6H, m), 1.2(6H, m).

Ex.23 (d⁶ -DMSO) δ8.0 (1H, t), 7.9 (1H, m), 7.4-7.0 (8H, m), 4.6 (2H,d), 3.9 (1H, m), 3.2 (1H, m), 3.1 (1H, m), 2.9 (1H, m), 2.5 (1H, m), 1.9(3H, s), 1.6 (6H, q), 1.4 (6H, s), 1.2 (3H, dd).

Ex.24 (CDCl₃) δ7.5-7.1 (8H, m), 6.2 (1H, t), 5.3 (1H, t), 4.5 (2H, s),3.7 (3H, s), 3.3 (2H, m) 3.2 (2H, q), 2.7 (2H, ddd), 2.4 (2H, t), 1.9(3H, s), 1.4 (6H, q), 1.2 (6H, s).

Ex.25 (CDCl₃) δ7.5-7.1 (8H, m), 5.9 and 5.7 (1H, 2×d), 5.3 and 5.1 (1H,2×t), 4.6 (2H, m), 4.3 (1H, m), 3.7 (3H, s), 3.3-3.1 (2H, dd), 2.9-2.5(2H, m), 1.9 (3H, s), 1.7 (6H, q), 1.3 (6H, d), 1.2 and 0.9 (3H, d).

Ex.26 (CDCl₃) δ7.5-7.1 (8H, m), 5.7 (1H, d), 5.3 (1H, t), 4.6 (2H, m),4.3 (1H, m), 3.7 (3H, s), 3.2 (2H, s), 2.8-2.6 (2H, dd), 1.9 (3H, s),1.7 (6H, q), 1.3 (6H, d), 1.1 (3H, d).

Ex.27 (CDCl₃) δ7.5-7.1 (8H, m), 6.1 (1H, t), 5.2 (1H, d), 4.6 (2H, m),4.2 (1H, m), 3.7 (3H, s), 3.2 (2H, dd), 2.8-2.5 (2H, dd), 1.9 (3H, s),1.6 (6H, q), 1.3 (6H, d), 0.9 (3H, d).

Ex.28 (CDCl₃) δ7.5-7.1 (8H, m), 6.1 and 5.9 (1H, 2×d), 5.4 and 5.2 (1H,2×t), 4.6 (2H, d), 4.3 (1H, m), 3.7 (3H, s), 3.2 (2H, ddd), 2.9-2.5 (2H,m), 2.0 (3H, s), 1.7 (6H, q), 1.3 (6H, d), 1.2 (3H, d).

Ex.29 (CDCl₃) δ7.5-7.1 (13H, m), 5.8 (1H, t), 5.2 (2H, s), 5.1(1H, t)4.6 (2H, d), 3.3 (2H, q), 3.3-3.0 (2H, q), 2.8-2.6 (2H, ddd), 2.4 (2H,q), 1.8 (3H, s), 1.7 (6H, q), 1.3 (6H, d).

Ex.30 (CDCl₃) δ7.6 (2H, d), 7.3-7.1 (7H, m), 4.8(1H, t) 4.6 (1H, d), 4.5(1H, d), 3.5 (1H, m), 3.3 (1H, d), 3.1 (2H, m), 2.9 (1H, q), 2.4 (3H,m), 1.9 (3H, s), 1.6 (6H, q), 1.2 (6H, d).

Ex.31 (d⁶ -DMSO) δ7.5-6.8 (12H, m), 4.5 (2H, m), 4.0 (1H, m), 3.3-2.5(4H, m), 1.9 (3H, s), 1.6 (6H, m), 1.4 and 1.3 (6H, 2×s), 1.1 and 1.0(3H, 2×d).

Ex.32 (d⁶ -DMSO) δ7.3 (4H, m), 7.1 (4H, m), 6.9-6.6 (2H, m), 4.5 and 4.3(1H, 2×t), 4.5 (2H, m), 3.6 (1H, m), 3.2 (1H, m), 3.0-2.8 (3H, m), 2.5(2H, m), 1.9 (3H, s), 1.6 (6H, m), 1.3 (6H, m), 0.9 and 0.8 (3H, 2×d).

Ex.33 (CDCl₃) δ7.4-7.1 (13H, m), 5.7 (1H, d), 5.3 (1H, t), 5.1 (2H, s),4.6 (1H, s), 4.5 (1H, s), 4.3 (1H, m), 3.2 (2H, s), 2.8 (1H, dd), 2.6(1H, dd), 1.9 (3H, s), 1.6 (6H, q), 1.3 (6H, d), 1.1 (3H, d).

Ex.34 (CDCl₃) δ7.5-7.1 (13H, m), 6.0 (1H, d), 5.1 (3H, m), 4.6 (2H, m),4.4 (1H, m), 3.3 (1H, dd), 3.2 (1H, dd), 2.9 (1H, dd), 2.5 (1H, dd), 2.0(3H, s), 1.7 (6H, q), 1.3 (9H, m).

Ex.35 (d⁶ -DMSO) δ7.5 (1H, d), 7.4-7.2 (4H, m), 7.0 (4H, m), 6.8 (1H,t), 4.5 (2H, s), 4.0 (1H, m), 3.0 (2H, m), 2.5 (2H, m), 1.8 (3H, s), 1.6(6H, q), 1.2 (6H, m), 1.1 (3H, d).

Ex.36 (d⁶ -DMSO) δ7.7 (1H, d), 7.3 (2H, m), 7.2 (2H, m), 7.1 (2H, m),7.0 (2H, m), 6.6 (1H, t), 4.5 (2H, s), 4.0 (1H, m), 3.0 (1H, d), 2.9(1H, d), 2.6 (2H, m), 1.9 (3H, s), 1.6 (6H, q), 1.3 (6H, m), 1.1 (3H,d).

Ex.37b (d⁶ -DMSO) δ7.6 (1H, t), 7.3 (2H, m), 7.0 (4H, m), 4.8 (1H, d),4.6 (1H, d), 3.7 (6H, 2×s), 3.1 (1H, dd), 2.7-2.4 (3H, m), 1.9 (3H, s),1.6 (6H, q), 1.4 (6H, m).

Ex.38 (d⁶ -DMSO) δ7.4 (1H, t), 7.3 (2H, m), 7.0 (2H, m), 6.6 (2H, m),4.8 (1H, d), 4.7 (1H, d), 3.7 (6H, 2×s), 3.1 (1H, dd), 2.7-2.4 (3H, m),1.9 (3H, s), 1.6 (6H, q), 1.4 (6H, m).

Ex.39 (d⁶ -DMSO) δ11.6 (1H, bs), 7.8 (1H, t), 7.3 (3H, m), 7.0 (5H, m),4.5 (1H, d), 4.4 (1H, d), 3.1 (2H, m), 2.9 (1H, m), 2.7 (1H, dd),2.0-1.4 (15H, m).

Ex.40 (d⁶ -DMSO) δ7.7 and 7.5 (1H, 2×d), 7.4-7.0 (8H, m), 6.8 and 6.7(1H, 2×t), 4.5 (1H, m), 4.4 (2H, s), 3.0-2.7 (8H, m), 2.5 (2H, m), 1.9(3H, s), 1.6 (6H, m), 1.3 (6H, 2×s), 1.1 and 1.0 (3H, 2×d).

Ex.41 (CDCl₃) δ7.5-7.1 (8H, m), 6.0 and 5.7 (1H, 2×d), 5.4 and 5.0 (1H,2×t), 4.6 (2H, m), 4.3 (1H, m), 3.7 (3H, s), 3.3-3.1 (2H, m), 3.0-2.6(2H, m), 1.6-1.4 (5H, m), 1.2-1.1 (7H, m), 0.7 (2H, m).

Ex.42 (CDCl₃) δ7.6 (1H, m), 7.3-7.0 (7H, m), 4.6 (3H, m), 4.3 (1H, m),3.7 (3H, s), 3.5-3.3 (3H, m), 3.0 and 2.8 (3H, 2×s), 2.8 (1H, m), 2.3(1H, m), 1.9 (3H, s), 1.6 (6H, q), 1.1 (6H, d).

Ex.43 (CDCl₃) δ7.6 (1H, m), 7.3-7.0 (7H, m), 4.6 (3H, m), 4.3 (1H, m),4.2 (2H, m), 3.5-3.3 (3H, m), 3.0 and 2.8 (3H, 2×s), 2.8 (1H, m), 2.4(1H, m), 1.9 (3H, s), 1.6 (6H, q), 1.3 (3H, m), 1.1 (6H, d).

Ex.44a (d⁶ -DMSO) δ12.7 (1H, s), 7.4-7.1 (8H, m) 4.8 (2H, m), 4.0 (2H,m) 3.2 (1H, dd), 3.15 (1H, dd), 1.43 (3H, t).

Ex.44b (d⁶ -DMSO) δ8.1 (1H, t), 7.4-7.0 (8H, m), 4.7 (1H, d), 4.65 (1H,d), 4.0 (2H, m), 3.4 (1H, dd), 3.1 (1H, dd), 2.9 (1H, dd), 2.6 (1H, dd),1.9-1.4 (15H, m), 1.1 (3H, t).

Ex.44c (d⁶ -DMSO) δ15-13 (1H, br s), 7.5-7.0 (9H, m), 4.8 (2H, s), 3.2(2H, s), 2.7 (2H, s), 1.7-0.9 (15H, m).

Ex.45 (CDCl₃) δ7.3 (4H, m), 7.1 (4H, m), 4.6 (2H, m), 3.5 (3H, s),3.4-3.6 (2H, m), 3.2 (1H, 2×s), 2.0 (3H, br s), 1.7 (6H, q), 1.4 (6H,d).

Ex.46 (CDCl₃) δ7.6 (1H, m), 7.3 (13H, m), 5.4-5.0 (2H, m), 4.9-4.4 (3H,m), 3.7-3.1 (4H, m), 3.0-2.2 (2H, m), 2.2-1.8 (7H, m), 1.6 (6H, q), 1.2(6H, m).

Ex.47 (CDCl₃) δ7.6 (1H, m), 7.3 (13H, m), 5.4-5.0 (2H, m), 4.9-4.4 (3H,m), 3.7-3.1 (4H, m), 3.0-2.2 (2H, m), 2.2-1.8 (7H, m), 1.6 (6H, q), 1.2(6H, m).

Ex.48 (CDCl₃) δ7.6 (1H, m), 7.3 (7H, m), 5.3 (1H, br s), 4.7-4.2 (3H,m), 3.8-3.2 (5H, m), 3.1 and 2.8 (1H, m) 2.3 (2H, m), 2.0 (5H, m), 1.6(6H, q), 1.2 (6H, m).

Ex.49 (CDCl₃) δ7.6 (1H, m), 7.3 (7H, m), 5.3 (1H br s), 4.7-4.2 (3H, m),3.8-3.2 (5H, m), 3.1 and 2.8 (1H, m) 2.3 (2H, m), 2.0 (5H, m), 1.6 (6H,q), 1.2 (6H, m).

Ex.50 (CDCl₃) δ7.6 (1H, m), 7.3 (7H, m), 4.7-4.3 (4H, m), 3.8-3.2 (7H,m), 3.0 and 2.8 (1H, m), 2.4-1.8 (8H, m), 1.6 (6H, q), 1.2 (6H, m).

Ex.51 (CDCl₃) δ7.6 (1H, m), 7.3 (7H, m), 4.7-4.3 (4H, m), 3.8-3.2 (7H,m), 3.0 and 2.8 (1H, m), 2.4-1.8 (8H, m), 1.6 (6H, q), 1.2 (6H, m).

Ex.52 (d6-DMSO) δ10.8 (1H,s), 7.5 (1H, d), 7.3 (6H, m), 7.0 (7H, m), 6.5(1H, m), 4.5 (1H, m), 4.4 (1H, m), 3.1 (2H, s), 3.0 (1H, dd), 2.9 (1H,dd), 2.7 (2H, m), 2.5 (2H, m), 1.8 (3H, s), 1.6 (6H, q), 1.3 (6H, d).

Ex.53 (d6-DMSO) δ10.9 (1H, 2×s), 7.9 and 7.6 (1H, 2×d), 7.5-7.2 (6H, m),7.1 (7H, m), 6.6 (1H, m), 4.5 (2H, m), 4.3 (1H, m), 3.5 (3H, s), 3.0(4H, dd), 2.5 (2H, m), 1.8 (3H, s), 1.6 (6H, q), 1.2 (6H, d).

Ex.54 (d⁶ -DMSO) δ10.9 (1H, 2×s), 7.9 and 7.6 (1H, 2×d), 7.5-7.2 (6H,m), 7.1 (7H, m), 6.6 (1H, m), 4.5 (2H, m), 4.3 (1H, m), 3.5 (3H, s), 3.0(4H, dd), 2.5 (2H, m), 1.8 (3H, s), 1.6 (6H, q), 1.2 (6H, d).

Ex.55a (diastereomer 1, higher R_(f)) (d⁶ -DMSO) δ10.9 (1H, s), 7.5-6.9(19H, m), 6.7 (1H, m), 4.9 (2H, m), 4.5 (2H, m), 4.3 (1H, m), 3.0 (4H,m), 2.5 (2H, m), 1.8 (3H, s), 1.6 (6H, q), 1.2 (6H, d).

Ex.55a (diastereomer 2, lower R_(f)) (d⁶ -DMSO) δ10.8 (1H, s), 7.9 (1H,d), 7.4-6.9 (18H, m), 6.6 (1H, m), 5.0 (2H, m), 4.5 (1H, s), 4.42 (1H,s), 4.38 (1H, m), 3.1-2.9 (4H, m), 2.5 (2H, m), 1.8 (3H, s), 1.6 (6H,q), 1.2 (6H, d).

Ex.55b (d⁶ -DMSO) δ10.9 (1H, s), 7.5 (2H, m), 7.4-6.9 (12H, m), 6.6 (1H,t), 4.4 (2H, m), 4.2 (1H, s), 3.0 (4H, m), 2.5 (2H, m), 1.9 (3H, s), 1.6(6H, q), 1.2 (6H, m).

Ex.56 (d⁶ -DMSO) δ10.8 (1H, s), 7.8 (1H, d), 7.4-6.9 (13H, m), 6.5 (1H,t), 4.5 (1H, s), 4.4 (1H, s), 4.3 (1H, m), 3.1 (1H, m), 3.0 (1H, dd),2.9 (2H, m), 2.4 (2H, m), 1.8 (3H, s), 1.6 (6H, q), 1.2 (6H, m).

Ex.57 (d⁶ -DMSO) δ10.9 (1H, s), 7.6 (2H, m), 7.4-6.9 (12H, m), 6.6 (1H,t), 4.4 (2H, m), 4.2 (1H, s), 3.0 (4H, m), 2.5 (2H, m), 1.8 (3H, s), 1.6(6H, q), 1.2 (6H, m).

Ex.58 (CDCl₃) δ8.1 (1H, s), 7.6 (1H, d), 7.4-6.9 (11H, m), 6.6 (1H, m),6.5 (1H, m), 5.5 (1H, m), 4.8 (1H, m), 4.4 (1H, s), 4.2 (1H, m), 3.2(4H, m), 2.7 (1H, m), 2.3 (1H, m), 2.0 (3H, s), 1.6 (6H, q), 1.2 (6H,m).

Ex.59 (d⁶ -DMSO) δ8.6 (1H, t), 7.3-7.0 (9H, m), 6.4 (1H, d), 6.2 (1H,d), 4.6 (2H, dd), 4.2 (2H, m), 3.2 (2H, d), 2.9 (1H, m), 2.5 (1H, m),1.9 (3H, s), 1.6 (6H, q), 1.4 (6H, d).

Ex.60 (CDCl₃) δ7.7 (1H, d), 7.4 (1H, d), 7.3-7.0 (9H, m), 4.9 (1H, s),4.7 (1H, d), 4.6 (1H, t), 3.9 (3H, m), 3.3 (2H, s), 2.6 (1H, q), 2.2(1H, q), 1.7 (3H, s), 1.5 (6H, q), 0.9 (6H, s).

Ex.61 (CDCl₃) δ7.6-7.0 (13H, m), 6.1 and 5.8 (1H 2×d), 5.5 and 5.3 (1H,2×t), 5.1 (2H, m), 4.6-4.2 (3H, m), 3.3-3.1 (2H, m), 2.9 (1H, m), 2.6(1H, m), 1.9 (4H, s), 1.6 (6H, m), 0.8-0.6 (6H, m).

Ex.62 (CDCl₃) δ7.5-7.1 (8H, m), 6.9 and 6.5 (1H 2×m), 5.5 and 5.4 (1H,2×m), 4.5 (2H, m), 4.3 and 4.2 (1H, m), 3.3 (2H, m), 3.0-2.4 (2H, m),2.0 (4H, s), 1.6 (6H, m), 1.3 (6H, m), 0.8 (6H, m).

Ex.63 (CDCl₃) δ7.5-7.2 (8H, m), 5.9 and 5.7 (1H 2×d), 5.3 and 5.2 (1H,m), 4.6 (2H, bt), 4.2 (1H, m), 3.7 (3H, d), 3.3 (2H, m), 2.9 and 2.6(2H, m), 1.9 (4H, s), 1.6 (6H, m), 1.3 (6H, m), 0.98-0.76 (6H, m).

Ex.64b (d⁶ -DMSO) δ12.4 (1H, br s), 7.8-6.8 (11H, m), 4.4 (2H, m), 4.2(1H, m), 3.0 (2H, m), 2.6-2.3 (4H, m), 1.9 (3H, s), 1.6 (6H, m), 1.3(6H, m).

Ex.65 (d⁶ -DMSO) δ12.6 (1H, br s), 7.9-6.9 (14H, m), 6.6 and 6.5 (1H,2×t), 4.5 (2H, m), 4.4 (1H, m), 3.0 (2H, m), 2.8-2.3 (4H, m), 1.9 (3H,s), 1.6 (6H, m), 1.3 (6H, m).

Ex.66 (d⁶ -DMSO) δ7.3-7.0 (10H, m), 4.5 (1H, s), 4.4 (1H, s), 3.6 (3H,s), 3.0 (2H, m), 2.7 (1H, m), 2.5 (1H, m), 1.9 (3H, s), 1.6 (6H, m), 1.3(6H, m), 1.1 (6H, 2×s).

Ex.67 (d⁶ -DMSO) δ7.4-7.0 (10H, m), 4.5 (1H, s), 4.4 (1H, s), 3.1 (1H,m), 2.9 (1H, m), 2.7 (1H, m), 2.5 (1H, m), 1.9 (3H, s), 1.6 (6H, m), 1.3(6H, m), 1.1 (6H, 2×s).

Ex.68 (CDCl₃) δ7.6 (1H, m), 7.4-7.0 (7H, m), 5.8 (1H, br s), 4.9-4.3(5H, m), 3.7-3.1 (4H, m), 2.9-2.1 (4H, m), 2.0 (3H, s), 1.6 (6H, m), 1.3(6H, m).

Ex.69 (CDCl₃) δ7.6 (1H, d), 7.4-7.1 (8H, m), 4.7 (1H, t), 4.6 (1H, d),4.5 (1H, d), 4.4 (2H, m), 3.8 (1H, m), 3.6 (1H, d), 3.4 (1H, dd), 3.2(1H, d), 2.8 (1H, dd), 2.4 (2H, m), 2.2 (1H, m), 2.0 (3H, s), 1.6 (6H,m), 1.3 (6H, m).

Ex.70 (CDCl₃) δ7.6 (1H, m), 7.4-7.0 (7H, m), 5.8 (1H, br s), 4.9-4.3(5H, m), 3.7-3.1 (4H, m), 2.9-2.1 (4H, m), 2.0 (3H, s), 1.6 (6H, m), 1.3(6H, m).

Ex.71 (CDCl₃) δ7.6 (1H, d), 7.4-7.1 (8H, m), 4.7 (1H, d), 4.6 (1H, d),4.4 (3H, m), 3.8 (3H, s), 3.7 (1H, m), 3.6-3.2 (4H, m), 2.8 (1H, dd),2.4 (1H, dd), 2.1 (1H, m), 1.9 (3H, s), 1.6 (6H, m), 1.2 (6H, m).

Ex.72 (CDCl₃) δ7.6 (1H, m), 7.4-7.0 (8H, m), 4.8-4.4 (5H, m), 3.9-3.1(8H, m), 2.9-2.1 (3H, m), 2.0 (3H, s), 1.6 (6H, m), 1.3 (6H, m).

Ex.73 (CDCl₃) δ7.6 (1H, m), 7.4-7.0 (8H, m), 4.8-4.4 (4H, m), 3.9-3.7(3H, m), 3.3-2.6 (3H, m), 2.5-2.1 (3H, m), 2.0 (3H, s), 1.6 (8H, m), 1.1(6H, m).

Ex.74 (CDCl₃) δ7.6 (1H, m), 7.4-7.0 (8H, m), 4.8-4.2 (4H, m), 3.9-2.1(12H, m), 2.0 (3H, s), 1.6 (8H, m), 1.1 (6H, m).

Ex.75 (CDCl₃) δ7.5-7.1 (8H, m), 6.2 and 6.1 (1H, 2×d), 5.4 and 5.3 (1H,2×t), 4.5 (3H, s), 3.3-3.1 (2H, m), 2.7 (2H, m), 1.9 (3H, s), 1.7 (6H,m), 1.3 (9H, m).

Ex.76 (CDCl₃) δ7.5-7.1 (8H, m), 6.2 and 5.9 (1H, 2×d), 5.4 and 5.2 (1H,2×t), 4.6 (2H, m), 4.3 (1H, m), 3.2 (2H, m), 2.9-2.4 (2H, m), 2.1 (3H,s), 1.9 (3H, s), 1.7 (6H, m), 1.3 (9H, m).

Ex.77 (CDCl₃) δ7.5-7.0 (8H, m), 6.2 and 5.8 (1H, 2×d), 5.4 and 5.1 (1H,2×t), 4.6 (2H, m), 4.3 (1H, m), 4.1 (2H, m), 3.5-3.2 (2H, m), 2.8 (1H,m), 2.6 (1H, m), 1.9 (3H, s), 1.7 (8H, m), 1.2 (9H, m), 0.9 (3H, m).

Ex.78 (CDCl₃) δ7.6 (1H, d), 7.4-7.1 (8H, m), 4.6-4.2 (3H, m), 3.6-3.2(5H, m), 2.8 (1H, dd), 2.4 (2H, m), 2.0 (5H, m), 1.6 (6H, m), 1.3 (6H,m).

Ex.79 (CDCl₃) δ7.6-7.1 (8H, m), 5.4 (1H, br s), 4.86-4.4 (3H, m),3.7-2.8 (6H, m), 2.4 (2H, m), 2.0 (5H, m), 1.6 (6H, m), 1.3 (6H, m).

Ex.80 (CDCl₃) δ7.6 (1H, d), 7.4-7.1 (7H, m), 4.6-4.3 (4H, m), 3.8 (3H,s), 3.5 (3H, m), 3.2 (1H, dd), 2.8 (1H, dd), 2.4 (1H, dd), 2.0 (7H, m),1.6 (6H, m), 1.2 (6H, s).

Ex.81 (CDCl₃) δ7.6-7.1 (8H, m), 4.8-4.4 (4H, m), 3.7 and 3.6 (3H, 2×s),3.5-2.9 (5H, m), 2.4-1.8 (8H, m), 1.6 (6H, m), 1.2 (6H, m).

Ex.82 (d⁶ -DMSO) δ7.6-6.9 (8H, m), 4.5 (2H, m), 4.1 (1H, m), 3.7-3.3(2H, m), 3.1 (2H, m), 2.5 (2H, m), 1.9 (3H, s), 1.6 (6H, m), 1.2 (6H,m).

Ex.83 (d⁶ -DMSO) δ7.7-6.9 (8H, m), 4.5 (2H, m), 4.1 (1H, m), 3.6-3.3(2H, m), 3.1 (2H, m), 2.6 (2H, m), 1.9 (3H, s), 1.6 (6H, m), 1.2 (6H,m).

Ex.84 (CDCl₃) δ7.6 (1H, d), 7.3-7.1 (7H, m), 6.6 (1H, d), 5.9 (1H, t),4.6 (1H, d), 4.4 (2H, m), 3.8 (3H, s), 3.7 (2H, m), 3.6 (1H, m) 3.2 (1H,dd), 3.0 (1H, dd), 2.9 (1H, dd), 2.7 (1H, dd), 2.0 (3H, s), 1.7 (6H, m),1.4 (6H, m).

Ex.85 (CDCl₃) δ7.5-7.1 (8H, m), 6.5 (1H, d), 5.6 (1H, t), 4.5 (2H, 2×s),4.4 (1H, m), 3.7 (6H, m), 3.3 (1H, dd), 3.2 (1H, dd), 2.9 (1H, dd), 2.5(1H, dd), 2.0 (3H, s), 1.7 (6H, m), 1.3 (6H, m).

Ex.86 (CDCl₃) δ7.7-7.1 (8H, m), 6.4 (1H, s), 5.8 (1H, s), 5.3 (1H, s),5.0 (1H, t), 4.6 (1H, d), 4.5 (1H, d), 3.8 (3H, s), 3.4 (1H, dd), 3.2(1H, dd), 2.7 (1H, dd), 2.5 (1H, dd), 1.9 (3H, s), 1.6 (6H, m), 1.2 (6H,s).

Ex.87 (d⁶ -DMSO) δ8.0-6.9 (9H, m), 4.9 amd 4.8 (1H, 2×m), 4.6-4.3 (3H,m), 3.5-2.7 (7H, m), 2.5-2.2 (2H, m), 1.8 (3H, s), 1.5 (6H, m), 1.1 (6H,m).

Ex.88 (CDCl₃) δ7.6 (1H, m), 7.4-7.0 (8H, m), 5.5-5.2 (1H, m), 4.6-4.4(3H, m), 3.7-3.2 (3H, m), 3.1-2.6 (2H, m), 2.3 (2H, m), 1.9 (3H, s), 1.6(6H, m), 1.4 (5H, m), 1.2 (6H, m).

Ex.89 (CDCl₃) δ7.6 (1H, m), 7.4-7.0 (7H, m), 5.3-4.3 (4H, m), 3.8-2.6(8H, m), 2.3 (2H, m), 1.9 (3H, s), 1.6 (6H, m), 1.4 (5H, m), 1.2 (6H,m).

Ex.90 (d⁶ -DMSO) δ8.1-6.9 (9H, m), 4.9-4.1 (5H, m), 3.7-3.1 (7H, m),2.9-2.1 (4H, m), 2.0 (3H, s), 1.6 (6H, m), 1.3 (6H, m).

Ex.91 (d⁶ -DMSO) δ8.1-6.9 (9H, m), 4.9-4.1 (5H, m), 3.8-3.1 (7H, m),2.9-2.1 (4H, m), 2.0 (3H, s), 1.6 (6H, m), 1.1 (6H, m).

Ex.92 (d⁶ -DMSO) δ7.5-7.0 (13H, m), 6.4 (1H, d), 5.2 (1H, t), 4.5 (3H,m), 3.7 (3H, s), 3.6 (2H, s), 3.2 (2H, dd), 2.6 (4H, m), 2.0 (3H, s),1.6 (6H, m), 1.2 (6H, s).

Ex.93 (CDCl₃) δ7.4-6.9 (13H, m), 6.3 (1H, d), 5.2 (1H, t), 4.5 (3H, m),3.6 (3H, s), 3.5 (2H, s), 3.1 (2H, dd), 2.6 (4H, m), 1.9 (3H, s), 1.6(6H, m), 1.2 (6H, s).

Ex.94 (d⁶ -DMSO) δ7.3 (3H, m), 7.1 (6H, m), 4.9-4.5 (3H, m), 3.3 (1H,m), 3.0 (1H, m), 2.8-2.5 (5H, m), 1.9 (3H, s), 1.6 (6H, m), 1.4 (6H, m),1.1 (3H, m).

Ex.95 (d⁶ -DMSO) δ7.3 (3H, m) 7.1-6.9 (6H, m), 4.9-4.5 (3H, m), 3.3 (1H,m), 3.0 (1H, m), 2.8-2.5 (5H, m), 1.9 (3H, s), 1.6 (6H m), 1.4 (6H, m),1.1 (3H, m).

Ex.96 (d⁶ -DMSO) δ7.4 (3H, m), 7.1 (5H, m), 5.0-4.4 (3H, m), 3.6 and 3.5(3H, 2×s), 3.2 (1H, m), 3.0 (1H, m), 2.8 and 2.7 (3H, 2×s), 2.5 (2H, m),1.9 (3H, s), 1.6 (6H, m), 1.3 (6H, m), 1.2-0.9 (3H, m).

Ex.97 (d⁶ -DMSO) δ7.4 (3H, m), 7.1-6.9 (5H, m), 5.0-4.3 (3H, m), 3.6 and3.5 (3H, 2×s), 3.3 (1H, m),3.0 (1H, m), 2.8-2.5 (5H, m), 1.9 (3H, s),1.6 (6H, m), 1.3-1.0 (9H, m).

Ex.98 (CDCl₃) δ7.7 (1H, d), 7.4-7.1 (7H, m), 4.6 (2H, m), 4.5 (1H, t),3.5 (1H, m), 3.4 (2H, m), 3.3 (2H, m), 3.1 (1H, m), 2.7 (1H, q), 2.4(1H, q), 1.9 (3H, s), 1.9-1.8 (4H, m), 1.6 (6H, m), 1.2 (6H, m).

Ex.99 (d⁶ -DMSO) δ7.4-7.0 (9H, m), 6.4 (1H, t), 4.4 (2H, m), 3.3 (1H,d), 3.1 (1H, dd), 2.9 (1H, dd), 2.5 (1H, q), 2.4 (3H, d), 1.9 (3H, s),1.6 (6H, m), 1.2 (6H, m).

Ex.100 (CDCl₃) δ7.7 (1H, d), 7.4-7.1 (7H, m), 4.6 (2H, m), 4.4 (1H, t),3.5 (1H, d), 3.1 (1H, dd), 2.9 (6H, 2×s), 2.7 (1H, dd), 2.5 (1H, dd),1.9 (3H, s), 1.6 (6H, m), 1.2 (6H, m).

Ex.101 (CDCl₃) δ7.4 (2H, m), 7.3-7.1 (6H, m), 5.9 (1H, m), 5.7 (1H, m),4.5 (2H, m), 3.2 (2H, d), 3.0 (2H, m), 2.6 (2H, m), 1.9 (3H, s), 1.6(6H, m), 1.2 (6H, m), 0.9 (3H, t).

Ex.102 (CDCl₃) δ7.5-7.1 (8H, m), 5.9 (1H, t), 5.3 (1H, d), 4.5 (2H, d),3.7 (2H, m), 3.1 (2H, s), 2.8 (1H, m), 2.6 (1H, m), 1.9 (3H, s), 1.6(6H, m), 1.2 (6H, m), 0.8 (6H, d).

Ex.103 (d⁶ -DMSO) δ7.4-7.0 (8H, m), 6.7 (1H, m), 6.6 (2H, m), 4.5 (2H,d), 3.0 (1H, d), 2.9 (1H, d), 2.6 (1H, m), 2.5 (1H, m), 1.9 (3H, s), 1.6(6H, m), 1.3 (6H, m).

Ex.104 (CDCl₃) δ7.7 (1H, m), 7.6 (1H, m), 7.4 (1H, m), 7.4-7.2 (10H, m),6.0 (1H, t), 5.3 (1H, t), 5.1 (2H, s), 4.5 (1H, d), 3.4 (1H, m), 3.3(2H, dt), 3.1 (1H, dd), 2.8 (1H, dd), 2.7 (1H, dd), 2.4 (2H, t), 1.9(3H, s), 1.6 (6H, m), 1.3 (6H, s).

Ex.105 (CDCl₃) δ7.8 (1H, m), 7.7 (1H, m), 7.4 (1H, m), 7.4-7.2 (10H, m),6.3 (1H, t), 5.2 (1H, t), 5.1 (2H, s), 4.6 (1H, d), 3.4 (1H, m), 3.3(2H, dd), 3.2 (1H, d), 2.8 (1H, dd), 2.7 (1H, dd), 2.4 (2H, t), 1.9 (3H,s), 1.6 (6H, m), 1.3 (6H, m).

Ex.106 (CDCl₃) δ7.5-7.1 (8H, m), 6.3-6.0 (1H, 2×d), 5.6 and 5.3 (1H,2×t), 4.6 (2H, m), 4.3 (1H, m), 3.7 (3H, m), 3.3 (2H, m), 2.9 (1H, m),2.7 (1H, m), 1.2 (3H, dd), 0.8 (9H, d).

Ex.107 (d⁶ -DMSO) δ8.0-6.9 (9H, m), 4.5-3.9 (3H, m), 3.5-2.6 (6H, m),2.2-1.6 (4H, m), 0.8 (9H, d).

Ex.108 (CDCl₃) δ7.4 (4H, m), 7.0 (4H, m), 5.7 (2H, d), 5.2 (1H, d), 3.0(2H, d), 2.0 (3H, s), 1.7 (6H, q), 1.5 (6H, s).

Ex.109 (CDCl₃) δ7.4-7.1 (8H, m), 5.0 (1H, t), 4.6 (1H, d), 4.4 (1H, d),2.8 (3H, m), 2.2 (1H, m), 1.9 (4H, m), 1.6 (6H, m), 1.3 (6H, s).

Ex.110 (CDCl₃) δ7.4-7.0 (8H, m), 4.7 (1H, d), 4.4 (1H, t), 3.6 (2H, dd),3.0 (1H, m), 2.2 (1H, m), 2.1 (1H, m), 2.0 (3H, s), 1.7 (6H, m), 1.5(6H, q).

Ex.111 (CDCl₃) δ7.5-7.1 (1H, m), 5.6 (1H, t), 4.6 (1H, s), 4.5 (1H, dd),4.3 (1H, m), 3.7 (3H, 2×s), 3.6 (1H, t), 3.4-3.1 (3H, m), 1.9 (3H, m),1.7 (6H, q), 1.4 (6H, s), 1.2 (3H, dd).

Ex.112 (CDCl₃) δ7.5-7.1 (8H, m), 5.6 (1H, t), 4.6 (1H, s), 4.5 (1H, dd),4.3 (1H, m), 3.8 (3H, 2×s), 3.6 (1H, t), 3.4-3.1 (3H, m), 1.9 (3H, m),1.7 (6H, q), 1.4 (6H, s), 1.2 (3H, dd)

Ex.113 (d⁶ -DMSO) δ7.4 (5H, m), 7.3 (4H, m), 7.1 (4H, m), 5.1 (2H, q),3.1 (2H, m), 2.8 (2H, q), 2.4 (2H, m), 1.8 (3H, s), 1.6 (6H, m), 1.2(6H, s).

Ex.114 (d⁶ -DMSO) δ7.7-6.8 (10 H, m), 4.6 (1H, s), 4.1 (1H, m), 3.6 (4H,m), 3.4 (1H, m), 2.7 (1H, q), 2.3 (1H, m), 1.8 (3H, s), 1.6 (6H, m), 1.3(6H, s), 1.2 (3H, d).

Ex.115 (d⁶ -DMSO) δ8.1-6.8 (10H, m), 4.6 (1H, s), 4.0 (1H, m), 3.6 (4H,m), 3.4 (1H, m), 2.7 (1H, q), 2.3 (1H, m), 1.8 (3H, s), 1.6 (6H, m), 1.3(6H, s), 1.2 (3H, m).

Ex.116 (d⁶ -DMSO) δ8.0-6.8 (10 H, m), 4.5 (1H, s), 4.0 (1H, m), 3.6 (4H,m), 3.4 (1H, m), 2.6 (1H, q), 2.3 (1H, m), 1.9 (3H, s), 1.6 (6H, m), 1.4(6H, s), 1.0 (3H, d).

Ex.117 (CDCl₃) δ8.6 and 8.2 (1H, 2×s), 7.5-7.1 (13H, m), 6.3 and 6.0(1H, 2×d), 5.4 and 5.2 (1H, 2×t), 4.8-4.4 (3H, m), 3.6 (3H, s), 3.3-2.3(6H, m), 0.8 (9H, 2×s).

Ex.118 (CDCl₃) δ8.2 -6.8 (15H, m), 5.6 and 5.4 (1H, 2×t), 4.8-4.2 (3H,m), 3.3-2.5 (6H, m), 0.8 (9H, 2×s).

Ex.119 (CDCl₃) δ7.6-7.0 (10H, m), 6.4 (1H, m), 5.0 (_1H, m), 4.6-4.4(2H, m), 4.3-4.0 (2H, m), 3.9-3.2 (3H, m), 2.9-2.6 (2H, m), 2.3 (1H, m),2.1-1.9 (7H, m), 1.6 (6H, m), 1.4 and 1.2 (6H, 2×s).

Ex.120 (CDCl₃) δ7.6-7.0 (10H, m), 6.1 (1H, m), 5.0-4.4 (3H, m), 4.2 (2H,m), 3.9-3.2 (3H, m), 2.9-2.6 (2H, m), 2.1-1.9 (8H, m), 1.6 (6H, m), 1.2(6H, s).

Ex.121 (CDCl₃) δ7.6-7.0 (10H, m), 6.1 (1H, s), 4.8-4.4 (3H, m), 4.2-3.3(5H, m), 2.9 (2H, m), 2.3 (1H, m), 2.1-1.9 (7H, m), 1.6 (6H, m), 1.2(6H, s).

Ex.122 (CDCl₃) δ7.6-7.1 (10H, m), 6.0 (1H, m), 4.8-4.3 (3H, m), 3.8-3.2(7H, m), 2.9 (1H, m), 2.6 (2H, m), 2.1-1.9 (7H, m), 1.6 (6H, m), 1.2(6H, s).

Ex.123 (CDCl₃ (δ7.6-7.1 (9H, m), 6.0 (1H, m), 4.6-4.0 (5H, m), 3.9-3.2(6H, m), 2.9-2.3 (3H, m), 2.1-1.9 (7H, m), 1.6 (6H, m), 1.4 and 1.2 (6H,2×s).

Ex.124 (CDCl₃) δ7.6-7.1 (9H, m), 5.9 (1H, m), 4.6-4.2 (3H, m), 3.8-3.1(8H, m), 3.0-2.2 (5H, m), 2.1-1.9 (7H, m), 1.6 (6H, m), 1.4 and 1.2 (6H,2×s).

Ex.125 (d⁶ -DMSO) δ7.7-7.5 (2H, m), 7.4-6.9 (9H, m), 4.5 (2H, m), 4.0(1H, m), 3.8-3.2 (4H, m), 2.8-2.6 (2H, m), 2.3 (2H, m), 1.9 (3H, m), 1.6(6H, m), 1.3 (6H, 2×s), 1.1 (3H, 2×d).

Ex.126 (CDCl₃) δ7.4-6.9 (9H, m), 5.9 (1H, m), 5.6 (1H, m), 4.5 (2H, m),4.2 (1H, m), 3.7 (3H, s), 3.4 (4H, m), 2.8 (2H, m), 2.5 (2H, m), 2.0(3H, s), 1.7 (6H, m), 1.3 (6H, 2×s), 1.1 (3H, 2×d).

Ex.127 (CDCl₃) δ7.5-7.1 (8H, m), 6.8 (1H, m), 6.1 and 5.9 (2H, m), 4.5(2H, m), 4.3 (1H, m), 3.2 (2H, s), 2.9-2.5 (5H, m), 2.0 (3H, s), 1.6(6H, m), 1.3 (9H, m).

Ex.128b (CDCl₃) δ7.5-7.1 (8H, m), 6.0 and 5.4 and 5.3 and 5.2 (2H, 4×d),4.6 (2H, m), 4.3 (1H, m), 3.7 (3H, 2×d), 3.5 (1H m), 3.2 (2H, m), 2.0(3H, s), 1.6-0.9 (15H, m), 0.8 (3H, 2×d).

Ex.129 (CDCl₃) δ7.5-7.1 (8H, m), 6.2 and 6.0 and 5.3 and 5.2 (2H, 4×d),4.6 (2H, m), 4.4 (1H, m), 3.7 (3H, 2×s), 3.5 (1H, m), 3.2 (2H, m), 2.0(3H, m), 1.8-0.9 (15H, m), 0.8 (3H, 2×d).

Ex.130 (CDCl₃) δ7.5-7.1 (8H, m), 6.2 and 6.0 (1H, 2×d), 5.4 and 5.2 (1H,2×t), 4.6 (2H, m), 4.3 (1H, m), 3.3-3.1 (2H, m), 2.9-2.3 (4H, m), 2.0(3H, s), 1.6 (6H, m),1.3 (6H, 2×s), 1.1 (6H, m).

Ex.131b (d⁶ -DMSO) δ7.6-6.9 (9H, m), 4.6 (1H, s), 4.3 (1H, s), 3.6 (3H,s), 3.5 (1H, m), 2.9-2.5 (4H, m), 2.0 (3H, s), 1.6 (6H, m),1.3 (6H, s).

Ex.132 (d⁶ -DMSO) δ7.9 and 7.5 (1H, 2×d), 7.4-6.9 (9H, m), 4.4 (2H, m),4.2-4.0 (1H, m), 3.6 (3H, 2×s), 3.0 (4H, m), 2.0 (3H, s), 1.6 (6H,m),1.3 (6H, 2×s), 1.2 (3H, m).

Ex.133 (CDCl₃) δ7.6-7.1 (9H, m), 5.3 (2H, m), 4.6-4.2 (3H, m), 3.6-3.1(4H, m), 2.7 (1H, m), 2.1-1.2 (18H, m).

Ex.134d (d⁶ -DMSO) δ13.5-12.5 (1H, br s), 8.3 (1H, t), 7.4-7.0 (8H, m),5.7 (1H, s), 5.4 (1H, s), 2.8 (2H, m), 1.9 (3H, s), 1.6 (6H, m), 1.4(6H, m).

Ex.135 (d⁶ -DMSO) δ8.8 (1H, d), 8.1 (1H, t), 7.5-7.0 (8H, m), 5.59 (1H,s), 5.56 (1H, s), 4.4 (1H, m), 3.6 (3H, s), 2.9 (2H, d), 1.9 (3H, s),1.6 (6H, m), 1.4 (6H, m), 1.3 (3H, d).

Ex.136 (d⁶ -DMSO) δ12.6 (1H, br s),8.4 (1H, t), 8.1 (1H, t), 7.5-6.9(8H, m), 5.8 (1H, s), 5.4 (1H, s), 4.4 (1H, m), 3.9-3.5 (2H, m), 3.3-2.5(4H, m), 2.1-1.4 (13H, m), 1.3 (6H, m).

Ex.137d (CDCl₃) δ7.8 (4H, m), 7.3 (4H, m), 6.1 and 5.5 (1H, br s), 4.6and 4.33 (1H, dd), 3.9-2.3 (7H, m), 2.0 (6H, m), 1.7 (6H, m), 1.4 (6H,m).

Ex.138c (CDCl₃) δ7.6-7.0 (8H, m), 5.9 and 5.0 (1H, 2×d), 4.6-4.3 (5H,m), 3.8-3.1 (4H, m), 2.4-1.9 (2H, m), 1.8-1.0 (15H, m).

Ex.139 (CDCl₃) δ7.7-7.0 (8H, m), 4.6-4.3 (3H, m), 3.8-2.8 (7H, m), 2.3(2H, m), 1.9-1.0 (19H, m).

Ex.140 (CDCl₃) δ7.7-7.0 (8H, m), 4.6-4.0 (4H, m), 3.8-2.2 (8H, m), 1.9(4H, m), 1.6 (9H, m), 1.0 (6H, m).

Ex.141 (CDCl₃) δ7.6-7.0 (8H, m), 5.0-4.5 (3H, m), 4.3 and 4.2 (1H, 2×m),3.6-3.0 (5H, m), 2.7 (1H, m), 2.4 (1H, m), 2.2 (1H, m), 1.8 (7H, m), 1.6(6H, m), 1.2 (6H, m).

Ex.142 (CDCl₃) δ7.6 (1H, m), 7.2 (7H, m), 5.0-4.6 (3H, m), 4.3 and 4.1(1H, 2×m), 3.6-3.0 (5H, m), 2.9 (1H, m), 2.7 (1H, m), 2.4 (1H, m), 2.2(1H, m), 1.9 (6H, m), 1.6 (6H, m), 1.2 (6H, m).

Ex.143 (CDCl₃) δ7.6 (1H, m), 7.2 (7H, m), 4.6 (3H, m), 4.4 and 4.2 (1H,2m), 3.65 and 3.6 (3H, 2s), 3.5-3.0 (5H, m), 2.7 (1H, m), 2.3 (1H, m),2.1-1.4 (14H, m), 1.2 (6H, m).

Ex.144 (CDCl₃) δ7.6-7.1 (8H, m), 4.8-4.5 (3H, m), 4.4 and 4.2 (1H, 2m),3.6 (3H, m), 3.5-2.0 (7H, m), 2.0-1.4 (14H, m), 1.2 (6H, m).

Ex.145 (CDCl₃) δ7.6-6.9 (8H, m), 5.5 (1H, m), 4.7 (1H, t), 4.5 (2H, m),4.2 (1H, m), 3.7-3.2 (5H, m), 2.9 (1H, m), 2.7 (1H, m), 2.2-1.7 (7H, m),1.5 (9H, m), 1.2 (6H, m).

Ex.146 (CDCl₃) δ7.6-7.0 (8H, m), 6.3 (1H, m), 4.5 (2H, d), 4.3 (2H, m),3.8-3.2 (5H, m), 2.9 (1H, m), 2.6 (1H, m), 2.0 (7H, m), 1.7 (6H, m), 1.4(9H, m).

Ex.147 (CDCl₃) δ7.6-7.0 (8H, m), 6.1 (1H, m), 4.8-4.2 (4H, m), 3.6-3.2(5H, m), 2.9 (1H, m), 2.3 (1H, m), 2.2-1.8 (7H, m), 1.6 (9H, m), 1.2(6H, m).

Ex.148 (CDCl₃) δ7.8-7.0 (8H, m), 4.8-4.2 (5H, m), 3.7-3.3 (3H, m), 3.2(1H, m), 2.7 (1H, d), 2.6 (1H, m), 2.4 (1H, m), 2.2-1.2 (13H, m), 1.1(6H, m), 0.8 (3H, d).

Ex.149 (d⁶ -DMSO) δ12.5 (1H, br s), 7.4-6.8 (9H, m), 5.1-4.1 (5H, m),3.9 (1H, m), 3.7 (1H, m), 3.3-2.9 (4H, m), 2.5 (2H, m), 1.9 (3H, s), 1.6(6H, m), 1.3 (6H, m).

Ex.150 (d⁶ -DMSO) δ7.3 (3H, m), 7.1 (5H, m), 6.8-6.3 (1H, m), 4.5 (2H,s), 3.7-2.7 (7H, m), 2.5 (2H, m), 1.9 (5H, m), 1.6 (6H, m), 1.2 (6H, s).

Ex.151 (CDCl₃) δ7.7-7.1 (8H, m), 4.6 (2H, br,s), 4.5 (1H, m), 3.7 (3H,m), 3.65-2.0 (9H, m), 1.9 (3H, br,s), 1.6 (7H, m), 1.3 (1H, m), 1.1 (6H,s).

Ex.152 (CDCl₃) δ7.6 (1H, d), 7.2 (7H, m), 4,8-4.2 (3H, m), 4.1 (2H, m),3.9-2.0 (9H, m), 1.9 (3H, s), 1.6 (10H, m), 1.2 (3H, m), 1.1 (6H, s).

Ex.153 (CDCl₃) δ7.6 (1H, d), 7.2 (7H, m), 4.8-4.2 (3H, m), 4.1 (2H, m),3.9-2.0 (9H, m), 1.9 (3H, s), 1.6 (10H, m), 1.2 (3H, m), 1.1 (6H, s).

Ex.154b (CDCl₃) δ7.7 (1H, m), 7.2 (7H, m), 4.8-4.2 (3H, m), 3.8 (1H, m),3.62 and 3.64 (3H, 2×s), 3.6-2.0 (8H, m), 1.9 (3H, s), 1.6 (8H, m), 1.2(2H, m), 1.1 (6H, s).

Ex.155 (CDCl₃) δ7.7 (1H, m), 7.2 (7H, m), 4.6-4.2 (3H, m), 3.8 (1H, m),3.63 and 3.65 (3H, 2×s), 3.6-2.0 (8H, m), 1.9 (3H, s), 1.6 (10H, m), 1.1(6H, s).

Ex.156 (CDCl₃) δ7.7 (1H, m), 7.2 (7H, m), 4.8-4.2 (3H, m), 3.8 (1H, m),3.63 and 3.65 (3H, 2×s), 3.6-2.0 (8H, m), 1.9 (3H, s), 1.6 (8H, m), 1.3(2H, m), 1.1 (6H, s).

Ex.157 (CDCl₃) δ7.6 (1H, d), 7.2 (7H, m), 4.8-4.3 (3H, m), 3.8 (1H, m),3.63 and 3.65 (3H, 2×s), 3.6-2.0 (8H, m), 1.9 (3H, s), 1.6 (10H, m), 1.1(6H, s).

Ex.158 (d⁶ -DMSO) δ8.2 (1H, s), 7.3 (3H, m), 7.0 (5H, m), 6.7 (1H, t),4.47 and 4.48 (2H, 2×s), 3.9 (1H, m), 3.5-2.9 (4H, m), 2.6 (1H, m), 2.4(1H, m), 1.8 (4H, m), 1.6 (9H, m), 1.3 (8H, m), 1.0 (2H,s).

Ex.159 (d⁶ -DMSO) δ8.3 (1H, s), 7.3 (3H, m), 7.0 (5H, m), 4.50 and 4.52(2H, 2×s), 4.1 (1H, t), 3.4 (2H, m), 3.1 (1H, m), 2.9 (1H, d), 2.7 (2H,m), 1.9 (4H, m), 1.6 (9H, m), 1.3 (6H, m), 1.2(1H, m), 0.9 (1H, m), 0.7(2H,m).

Ex.160d (CDCl₃) δ7.7 (1H, d), 7.4-7.1 (6H, m), 6.9 (1H, m), 5.0 (1H, d),4.6 (1H, s), 4.3 (1H, m), 3.5 (3H, m), 3.3 (1H, m), 2.9 (1H, m), 2.5-1.4(14H, m), 1.2 (6H, m).

Ex.161 (CDCl₃) δ7.6 (1H, d), 7.4-7.0 (6H, m), 6.9 (1H, m), 5.0 (1H, s),4.6 (2H, m), 4.3 (1H, m), 3.5 (3H, m), 3.2 (2H, m), 2.8-1.4 (13H, m),1.2 (6H, m).

Ex.162 (CDCl₃) δ7.7 (1H, d), 7.4-7.1 (6H, m), 6.9 (1H, m), 5.0 (1H, m),4.6 (1H, m), 4.3 (1H, m), 3.5 (3H, m), 3.3 (1H, m), 2.9 (1H, m), 2.5-1.4(14H, m), 1.2 (6H, m).

Ex.163 (d⁶ -DMSO) δ8.2 (1H, t), 7.5 (1H, s), 7.3 (3H, m), 7.0 (5H, m),4.5 (2H, d), 4.0 (1H, m), 3.1-3.4 (2H, m), 3.0 (1H, m), 2.9 (1H, d),2.8-2.6 (2H, m), 1.9-1.3 (19H, m), 1.08 and 1.13 (6H, 2×s).

Ex.164 (d⁶ -DMSO) δ7.9(1H, s), 7.3-6.8 (1H, t), 4.5 (2H, s), 4.0 (1H,m), 3.1-3.4 (3H, m), 3.0 (1H, m), 2.85 (2H, m), 2.1 (1H, m), 2.0-1.0(24H, m).

Ex.165 (CDCl₃) δ7.7-6.9 (8H, m), 5.7 (1H, m), 5.4 (1H, m), 4.9-4.4 (2H,m), 3.8-2.4 (5H, m), 2.2-1.2 (19H, m).

Ex.166 (CDCl₃) δ7.5 (1H, m), 7.4-7.1 (7H, m), 5.4 and 5.1 (1H, 2×br,s),4.5 (2H, m), 4.4 (2H, m), 3.75 and 3.72 (3H, 2×s), 3.5 (2H, m), 2.8 (1H,m), 2.5 (1H, m), 1.9 (3H, br, s), 1.6 (6H, m), 1.2 (6H, m).

Ex.167 (d⁶ -DMSO) δ12.8 (1H, br s), 7.5 (1H, d), 7.4-6.9 (9H, m), 4.4(2H, s), 4.1 (1H, m), 3.8 (2H, m), 3.4 and 3.0 (2H, 2×dd), 3.1 and 2.8(2H, 2×dd), 2.5 (2H, m), 2.45 and 2.0 (2H, 2×dd), 1.9 (3H, s), 1.6 (6H,m), 1.3 (6H, s).

Ex.168 (d⁶ -DMSO) δ12.8 (1H, br s), 7.7 (1H, d), 7.4-6.9 (8H, m), 6.8(1H, t), 4.4 (2H, s), 4.1 (1H, m), 3.9 (2H, m), 3.5 and 3.1 (2H, 2×dd),2.9 (2H, 2×dd), 2.6 (2H, m), 2.4 and 1.9 (2H, 2×dd), 1.85 (3H, s), 1.6(6H, m), 1.3 (6H, s).

Ex.169 (d⁶ -DMSO) δ7.5 (1H, d), 7.4-6.9 (9H, m), 4.4 (2H, s), 4.2-3.8(3H, m), 3.6 (3H, s), 3.5-2.9 (4H, m), 2.8 (1H, d), 2.5 (2H, m), 2.0(1H, m), 1.9 (3H, s), 1.6 (6H, m), 1.3 (6H, s).

Ex.170 (d⁶ -DMSO) δ7.6 (1H, d), 7.4-6.9 (8H, m) 6.8 (1H, t), 4.4 (2H,s), 4.0 (3H, m), 3.6 (3H, s), 3.6-1.95 (8H, m), 1.9 (3H, s), 1.6 (6H,m), 1.3 (6H, s).

Ex.171 -DMSO) δ8.1 (1H, m), 7.9 and 7.5 (1H, 2×m), 7.4-6.9 (14H, m),4.6-4.2 (3H, m), 3.8-2.4 (8H, m), 1.9 (3H, br,s), 1.6 (6H, m), 1.3 (6H,m).

Ex.172 (d⁶ -DMSO) δ8.0-6.8 (16H, m), 4.5-4.0 (4H, m), 3.4-2.4 (6H, m),1.8 (3H, s), 1.6 (6H, m), 1.2 (6H, m), 1.1 (3H, d).

Ex.173 (d⁶ -DMSO) δ8.0-6.9 (16H, m), 4.5-4.0 (3H, m), 3.3-2.5 (8H, m),1.8 (3H, m), 1.6 (6H, m), 1.2 (6H, m).

Ex.174 (d⁶ -DMSO) δ10.85 and 10.8 (1H, 2×s), 8.1 (1H, m), 7.7-6.7 (15H,m), 4.5-4.1 (3H, m), 3.8-2.3 (8H, m), 1.9 (3H, m), 1.6 (6H, m), 1.2 (6H,m).

Ex.175 (CDCl₃) δ7.6-7.0 (8H, m), 4.8 (2H, m), 4.6 (2H, m), 4.3 (1H, m),3.6-2.2 (9H, m), 2.1-1.4 (13H, m), 1.2 (6H, s).

Ex.176 (CDCl₃) δ7.6-6.7 (8H, m), 4.8-4.0 (5H, m), 3.3-2.0 (9H, m),1.8-0.8 (19H, m).

Ex.177 (CDCl₃) δ7.1 (1H, m), 7.0-6.6 (8H, m), 5.6 (1H, br,s), 4.3 (1H,s), 4.1 (1H, s), 3.3 (1H, m), 2.9 (1H, d), 2.7 (1H, d), 0.9 (16H, m),0.6 (6H, t).

Ex.178 (d⁶ -DMSO) δ12.8 (1H, br s), 7.7 (1H, m), 7.4-6.9 (8H, m), 6.7and 6.6 (1H, 2×m), 4.4 (2H, m), 4.3-3.8 (3H, m), 3.4-2.8 (4H, m) 2.5(2H, m), 2.1 (1H, m), 1.9 (3H, s), 1.6 (7H, m), 1.3 (6H, m).

Ex.179 (d⁶ -DMSO) δ12.8 (1H, br s), 7.7 (1H, m), 7.5-7.0 (8H, m), 6.7and 6.6 (1H, 2×m), 4.4 (2H, m), 4.3-3.5 (3H, m), 3.4-2.9 (4H, m), 2.5(2H, m), 2.1 (1H, m), 1.9 (3H, s), 1.6 (7H, m), 1.3 (6H, m).

Ex.180 (d⁶ -DMSO) δ8.3-6.9 (10H, m), 4.5 (2H, m), 4.0-2.5 (8H, m), 1.9(4H, m), 1.7 (9H, m), 1.4-1.2 (9H, m).

Ex.181 (d⁶ -DMSO) δ8.3 and 8.25 (1H, 2t), 7.7-6.9 (10H, m), 6.6 and 6.5(1H, 2s), 4.5 (2H, m), 4.1 and 3.8 (1H, 2m), 3.6-2.4 (8H, m), 2.0-1.5(13H, m), 1.4 and 1.3 (6H, m).

Ex.182 (d⁶ -DMSO) δ8.1-6.8 (18H, m), 4.5-4.1 (3H, m), 3.6-2.4 (8H, m),1.9 (3H, sm), 1.6 (6H, m), 1.3 (6H, m).

Ex.183 (d⁶ -DMSO) δ12.0 (1H, br s), 7.9 (1H, m), 7.4 (4H, m), 7.1-6.8(5H, m), 4.6-4.3 (3H, m), 3.9 (1H, m), 3.7 (2H, m), 3.5-2.9 (5H, m), 2.6(2H, m), 1.9-1.5 (11H, m), 1.3 (6H, m).

Ex.184b (d⁶ -DMSO) δ12.6 (1H, br s), 8.1 and 6.3 (1H, 2×t), 7.4-6.9 (9H,m), 4.5 (2H, m), 4.2-3.9 (2H, m), 3.5-2.8 (6H, m), 2.6 (2H, m), 2.1-1.5(13H, m), 1.4-1.1 (9H, m).

Ex.185 (d⁶ -DMSO) δ12.6 (1H, br s), 8.0 and 6.3 (1H, 2×m), 7.4-6.9 (9H,m), 4.5 (2H, m), 4.2-3.9 (2H, m), 3.5-2.8 (6H, m), 2.6 (2H, m), 2.1-1.5(13H, m), 1.4-1.1 (9H, m).

Ex.186b (d⁶ -DMSO) δ12.5 (1H, br s), 8.2 and 8.0 (1H, 2×d), 7.4-6.9 (9H,m), 4.5 (2H, m), 4.1 (2H, m), 3.5-2.3 (8H, m), 2.2-1.5 (13H, m), 1.4-1.1(9H, m).

Ex.187 (d⁶ -DMSO) δ12.4 (1H, br s), 8.1 (1H, d), 7.3 (3H, m), 7.1 (5H,m), 4.5 (2H, d), 4.1 (1H, m), 3.9 (1H, m), 3.3-2.9 (6H, m), 2.5 (2H, m),2.1-1.4 (13H, m), 1.2 (9H, m).

Ex.188 (CDCl₃) δ9.1 and 6.0 (1H, 2×t), 7.6-7.0 (8H, m), 4.6-4.3 (3H, m),4.1 (1H, m), 3.8 and 3.3 (3H, 2×s), 3.6-3.1 (6H, m), 2.9 (1H, m),2.7-2.2 (2H, m), 2.0-1.6 (12H, m), 1.4 and 1.2 (6H, 2×s).

Ex.189 (CDCl₃) δ7.6-7.0 (8H, m), 5.9 (1H, m), 4.5 (3H, m), 4.1 (1H, m),3.7 (3H, s), 3.6-3.4 (4H, m), 3.3 (2H, s), 2.8 (1H, m), 2.6 (1H, m), 2.3(1H, m), 2.0-1.6 (12H, m), 1.4 (6H, s).

Ex.190 (d⁶ -DMSO) δ7.4-6.9 (8H, m), 6.8 (1H, t), 4.8-4.1 (3H, m),3.6-2.6 (9H, m), 2.5 (2H, m), 1.9-1.4 (13H, m), 1.2 (6H, m).

Ex.191 (d⁶ -DMSO) δ7.8 (1H, t), 7.5-6.9 (8H, m), 6.8 and 6.7 (1H, 2×t),4.8-3.8 (5H, m), 3.6 (3H, m), 3.4-2.9 (4H, m), 2.5 (2H, m), 2.1 (1H, m),1.9 (3H, br s), 1.7-1.2 (13H, m).

Ex.192 (CDCl₃) δ7.6-7.1 (8H, m), 5.1 and 4.7 (1H 2×m), 4.5 and 4.3 (1H,2×d), 3.5 (2H, m), 3.4-2.8 (4H, m), 2.4-1.1 (25H, m).

Ex.193 (CDCl₃) δ7.5 (1H, d), 7.4-7.1 (7H, m), 4.6 (1H, m), 4.2 (1H, m),3.5 (2H, m), 3.2 (2H, m), 2.9 (1H, m), 2.3 (1H, m), 2.2-1.8 (13H, m),1.6 (6H, m), 1.2 (6H, m).

Ex.194 (d⁶ -DMSO) δ12.5 (1H, br s), 8.1 (1H, t), 7.3 (3H, m), 7.0 (5H,m), 6.3 (1H, t), 4.5 (2H, m), 3.9 (1H, m), 3.7 (2H, m), 3.4-2.9 (4H, m),2.7-2.3 (4H, m), 2.1 (1H, m), 1.8 (3H, s), 1.6 (9H, m), 1.3 (6H, s).

Ex.195 (CDCl₃) δ7.7-7.1 (8H, m), 6.9 and 6.0 (1H 2×t), 4.6(3H, m),4.4-4.0 (3H, m), 3.8 (1H, m), 3.5 (4H, m), 3.2 (2H, m), 2.8 (1H, m), 2.3(2H, m), 1.9 (6H, m), 1.8-1.2 (22H, m).

Ex.196 (CDCl₃) δ7.6 (1H, d), 7.5-7.1 (7H, m), 6.9 (1H, d), 5.8 and 5.2(2H, dd), 4.5(3H, m), 4.3 (1H, m), 3.5 (4H, m), 3.2 (1H, d), 2.9 (1H,m), 2.5-2.1 (2H, m), 2.0-1.1 (30H, m).

Ex.197 (d⁶ -DMSO) δ8.2 and 6.7 (1H,2×m), 7.4-6.8 (10H, m), 4.5 (2H, m),4.1 and 3.8 (1H, 2×m), 3.6-2.5 (6H, m), 1.9 (3H, m), 1.8-1.5 (10H, m),1.4 and 1.2 (6H, 2×s).

Ex.198b (d⁶ -DMSO) δ12.6 (1H, br s), 8.0 (1H, t), 7.4 (3H, m), 7.0 (6H,m), 4.5 (2H, d), 4.1 (1H, m), 3.6 (2H, m), 3.4-2.8 (4H, m), 2.6-2.2 (4H,m), 1.9 (3H, s), 1.6 (10H, m), 1.35 (6H, s).

Ex.199 (d⁶ -DMSO) δ12.6 (1H, br s), 8.1 (1H, t), 7.3 (3H, m), 7.0 (5H,m), 6.4 (1H, t), 4.5 (2H, m), 3.9 (1H, m), 3.6 (2H, m), 3.4-2.9 (4H, m),2.6-2.4 (4H, m), 2.1 (1H, m), 1.8 (3H, s), 1.6 (9H, m), 1.2 (6H, s).

Ex.200 (d⁶ -DMSO) δ12.6 (1H, br s), 8.0 (1H, d), 7.3 (3H, m), 7.0 (6H,m), 4.5 (2H, m), 4.0 (2H, m), 3.4-2.8 (4H, m), 2.6-2.1 (5H, m), 1.9 (3H,s), 1.6 (9H, m), 1.2 (9H, m).

Ex.201 (d⁶ -DMSO) δ12.6 (1H, br s), 8.0 (1H, d), 7.3 (3H, m), 7.0 (5H,m), 6.3 (1H, t), 4.5 (2H, d), 4.1 (1H, m), 3.9 (1H, m), 3.4-2.9 (4H, m),2.6-2.4 (4H, m), 2.0 (1H, m), 1.9 (3H, s), 1.6 (9H, m), 1.2 (9H, m).

Ex.202 (d⁶ -DMSO) δ12.6 (1H, br s), 8.0 (1H, d), 7.3 (3H, m), 7.0 (6H,m), 4.5 (2H, m), 4.1 (2H, m), 3.5-2.8 (4H, m), 2.7-2.2 (5H, m), 1.9 (3H,s), 1.6 (9H, m), 1.4-1.1 (9H, m).

Ex.203 (d⁶ -DMSO) δ12.6 (1H, br s), 8.1 (1H, d), 7.3 (3H, m), 7.0 (5H,m), 6.4 (1H, t), 4.5 (2H, d), 4.1 (1H, m), 3.9 (1H, m), 3.4-2.9 (4H, m),2.7-2.3 (4H, m), 2.0 (1H, m), 1.8 (3H, s), 1.6 (9H, m), 1.2 (9H, m).

Ex.204 (CDCl₃) δ7.6-7.1 (8H, m), 5.1-4.5 (3H, m), 4.0 (1H, m), 3.6-2.2(10H, m), 2.0-1.4 (13H, m), 1.2 (6H, m).

Ex.205 (CDCl₃) δ7.6 (1H, m), 7.4-7.0 (7H, m), 6.8 (1H, m), 5.8 (1H, dd),4.7-4.4 (4H, m), 3.8 and 3.75 (3H, 2×s), 3.6-2.2 (6H, m), 2.0-1.4 (13H,m), 1.2 (6H, m).

Ex.206 (CDCl₃) δ7.7-7.1 (8H, m), 4.5 (3H, m), 3.9 (1H, m), 3.7 and 3.6(3H, 2×s), 3.5-2.1 (10H, m), 2.0-1.5 (13H, m), 1.2 (6H, m).

Ex.207 (d⁶ -DMSO) δ8.0 (1H, t), 7.5 (1H, d), 7.4-6.8 (16H, m), 4.4 (2H,s), 4.1 (1H, m), 3.6-3.1 (3H, m), 2.9 (3H, m), 2.5 (2H, m), 1.9 (3H, s),1.6 (6H, m), 1.3 (6H, s).

Ex.208 (d⁶ -DMSO) δ8.0 (1H, t), 7.8 (1H, d), 7.5 (1H, t), 7.4-6.9 (15H,m), 4.5 (1H, s), 4.3 (1H, m), 4.2 (1H, s), 3.6-3.0 (4H, m), 2.7 (2H, m),2.5 (2H, m), 1.9 (3H, s), 1.6 (6H, m), 1.3 (6H, m).

Ex.209 (CDCl₃) δ7.4-7.0 (8H, m), 5.6 (1H, t), 4.6 (1H, s), 4.4 (1H, s),2.9 (3H, m), 2.3 (2H, dd), 2.0 (3H, s), 1.6 (6H, m), 1.3 (1H, d), 1.2(6H, s).

Ex.210 (CDCl₃) δ7.2 (8H, m), 7.1 and 6.2 (1H, 2×d), 5.7 and 5.6 (1H,2×t), 4.7-4.2 (3H, m), 3.7 (3H, s), 3.0-2.2 (5H, m), 2.0 (3H, s), 1.7(7H, m), 1.43 and 1.40 (6H, 2×s), 1.3 and 1.1 (3H, 2×d).

Ex.211 (CDCl₃) δ7.5-7.0 (8H, m), 5.8 and 5.6 (1H, 2×t), 4.8-4.3 (3H, m),3.9-3.2 (3H, m), 3.0 (3H, m), 2.6-1.0 (21H, m).

Ex.212 (CDCl₃) δ7.5 (1H, d), 7.4-7.1 (7H, m), 6.2 (1H, d), 5.8 (1H, t),4.5 (2H, d), 3.8 (1H, m), 3.2 (2H, dd), 2.8 (1H, m), 2.7 (1H, m), 2.4(1H, m), 2.0 (3H, s), 1.8-1.1 (18H, m).

Ex.213 (CDCl₃) δ7.5-7.1 (8H, m), 6.3 (1H, d), 5.7 (1H, t), 4.5 (2H, d),3.8 (1H, m), 3.2 (2H, dd), 2.8 (1H, m), 2.7 (1H, m), 2.5 (1H, m), 2.0(3H, s), 1.8-1.1 (18H, m).

Ex.214 (CDCl₃) δ7.6-6.8 (9H, m), 6.0 (1H, m), 4.8-4.2 (4H, m), 3.8 (3H,s), 3.6-2.1 (7H, m), 2.0-1.1 (21H, m).

Ex.215 (CDCl₃) δ7.6-7.1 (8H, m), 5.1-4.5 (3H, m), 4.0 (1H, m), 3.6-2.2(10H, m), 2.0-1.4 (13H, m), 1.2 (6H, m).

Ex.216 (d⁶ -DMSO) δ8.0-7.0 (15H, m), 6.8-6.5 (2H, m), 4.5-4.0 (3H, m),3.4-3.0 (4H, m), 2.5 (2H, m), 1.82 and 1.78 (3H, 2×s), 1.6 (6H, m), 1.1and 1.2 (6H, 2×s).

Ex.217 (d⁶ -DMSO) δ8.2-6.8 (16H, m), 6.5 (1H, t), 4.5-4.1 (3H, m),3.4-2.2 (6H, m), 1.8 and 1.7 (3H, 2×s), 1.6 (6H, m), 1.1 and 1.2 (6H,2×s).

Ex.218 (d⁶ -DMSO) δ8.0 (1H, t), 7.7 (1H, d), 7.4-6.7 (14H, m), 4.5-4.0(4H, m), 3.6-2.3 (6H, m), 1.8 (3H, s), 1.6 (6H, m), 1.3-1.0 (9H, m).

Ex.219 (d⁶ -DMSO) δ12.6 (1H, br s), 7.4-6.9 (13H, m), 5.0-4.0 (4H, m),3.6-3.0 (3H, m), 2.8-2.1 (4H, m), 1.7 (3H, br s), 1.6 (6H, m), 1.1 and1.08 (6H, 2×s).

Ex.220c (CDCl₃) δ7.6-7.0 (8H, m), 4.8-4.3 (3H, m), 3.8-2.3 (9H, m),2.2-1.4 (19H, m).

Ex.221 (CDCl₃) δ7.6-7.0 (8H, m), 6.4 (1H, m), 4.6-4.4 (2H, m), 4.3-4.0(1H, m), 3.9-3.1 (9H, m), 2.9-2.6 (2H, m), 2.3 (1H, m), 2.1-1.9 (6H, m),1.6 (6H, m), 1.4 and 1.2 (6H, 2×s).

Ex.222 (CDCl₃) δ7.6-6.9 (8H, m), 5.5 (1H, m), 4.5 (2H, m), 4.2 (1H, m),3.7-3.1 (8H, m), 2.9 (1H, m), 2.7 (1H, m), 2.2-1.7 (7H, m), 1.5 (9H, m),1.2 (6H, m).

Ex.223 (CDCl₃) δ7.6-7.0 (8H, m), 6.1 (1H, m), 4.7-4.2 (3H, m), 3.6-3.1(8H, m), 2.9 (1H, m), 2.3 (1H, m), 2.2-1.8 (7H, m), 1.6 (9H, m), 1.2(6H, m).

Ex.224b (d⁶ -DMSO) δ12.6 (1H, br s), 7.4-6.9 (9H, m), 4.5 (2H, m),4.2-3.9 (2H, m), 3.5-2.8 (9H, m), 2.6 (2H, m), 2.1-1.5 (13H, m), 1.4-1.1(9H, m).

Ex.225 (d⁶ -DMSO) δ12.6 (1H, br s), 7.4-6.9 (9H, m), 4.5 (2H, m),4.2-3.9 (2H, m), 3.5-2.8 (9H, m), 2.6 (2H, m), 2.1-1.5 (13H, m), 1.4-1.1(9H, m).

Ex.226b (d⁶ -DMSO) δ12.6 (1H, br s), 8.0 (1H, d), 7.3 (3H, m), 7.0 (5H,m), 4.5 (2H, d), 4.1 (1H, m), 3.9 (1H, m), 3.4-2.9 (7H, m), 2.6-2.4 (4H,m), 2.0 (1H, m), 1.9 (3H, s), 1.6 (9H, m), 1.2 (9H, m).

Ex.227 (CDCl₃) δ7.6-7.0 (9H, m), 6.0 (1H, m), 4.6-4.0 (5H, m), 3.8-3.2(6H, m), 2.9-2.2 (3H, m), 2.0-1.2 (19H, m).

Ex.228 (CDCl₃) δ7.8-7.1 (9H, m), 6.6 (1H, m), 4.6-4.2 (4H, m), 3.6-3.0(4H, m), 2.9-2.0 (3H, m), 2.0-1.2 (21H, m).

Ex.229 (CDCl₃) δ8.1 (1H, t), 7.6 (1H, d), 7.4-7.1 (7H, m), 6.0 (1H, t),4.8 (1H, m), 4.6 (1H, s), 4.4 (1H, s), 4.1 (1H, dd), 3.8 (1H, dd), 3.5(2H, m), 2.9-2.2 (6H, m), 2.0 (3H, s), 1.6 (6H, m), 1.4 (6H, s).

Ex.230 (CDCl₃) δ7.6-6.9 (9H, m), 5.8 (1H, m), 4.5 (2H, m), 4.2-3.6 (3H,m), 3.2 (2H, m), 2.5 (2H, m), 2.2-1.2 (19H, m).

Ex.231 (d⁶ -DMSO) δ12.6 (1H, br s), 8.1 (1H, d), 7.3 (3H, m), 7.0 (5H,m), 4.5 (2H, d), 4.1 (1H, m), 3.9 (1H, m), 3.4-2.9 (7H, m), 2.7-2.3 (4H,m), 2.0 (1H, m), 1.8 (3H, s), 1.6 (9H, m), 1.2 (9H, m).

Ex.232 (d⁶ -DMSO) δ12.5 (1H, br s), 8.2 and 8.0 (1H, 2×d), 7.4-6.9 (9H,m), 4.5 (2H, m), 4.1 (2H, m), 3.7 (3H, s), 3.5-2.3 (8H, m), 2.2-1.5(13H, m), 1.4-1.1 (9H, m).

Ex.233 (d⁶ -DMSO) δ12.6 (1H, br s), 8.6 and 8.4 (1H, 2×t), 8.2 and 7.8(1H, 2×t), 7.6 (1H,m), 7.3 (3H, m), 7.0 (4H, m), 5.0 and 4.7 (1H, 2×d),4.55 (2H, d), 4.5-4.1 (2H, m), 3.9-3.5 (4H, m), 3.3-2.4 (4H, m), 1.9(3H, s), 1.6 (6H, m), 1.3 (6H, m).

Ex.234 (d⁶ -DMSO) δ12.6 (1H, br s), 8.9 and 8.3 (1H, 2×m), 7.6 (1H, t),7.3 (3H, m), 7.0 (5H, m), 5.1 and 4.6 (1H, 2×m), 4.5 (1H, s), 4.4 (1H,s), 4.3-3.6 (6H, m), 3.4-2.2 (4H, m), 1.9 (3H, s), 1.6-1.3 (12H, m).

Ex.235 (d⁶ -DMSO) δ12.7 (1H, br s), 9.0 (1H, m), 8.6-8.2 (3H, m),7.7-6.9 (6H, m), 4.9-3.0 (9H, m), 2.8-2.2 (4H, m), 1.9 (3H, m), 1.6-1.3(12H, m).

Ex.236 (d⁶ -DMSO) δ9.4 (1H, s), 8.4 (2H, s), 8.3 (1H, t), 8.1 (1H, s),7.3 (3H, m), 7.1 (3H, m), 6.9 (2H, m), 4.6 (2H, s), 4.3 (1H, m), 3.5(2H, m), 3.1 and 3.0 (2H, 2×d), 2.8 and 2.6 (2H, m), 2.1-1.2 (19H, m).

Ex.237 (d⁶ -DMSO) δ11.7 (1H, s), 10.2 (1H, s), 8.44 (2H, s), 8.4 (1H,t), 8.1 (1H, s), 7.3 (3H, m), 7.1 (3H, m), 6.9 (2H, m), 4.5 (2H, s), 4.0(1H, m), 3.5 (2H, m), 3.1 and 3.0 (2H, 2×d), 2.8-2.5 (2H, m), 2.0-1.1(19H, m).

Ex.238 (d⁶ -DMSO) δ8.1 and 8.0 (1H, 2×d), 7.3 (3H, m), 7.0 (5H, m), 7.0and 6.3 (1H, 2×t), 4.5 (2H, m), 4.2-2.1 (12H, m), 2.0-1.1 (22H, m).

Ex.239a (d⁶ -DMSO) δ7.5 (2H, m), 7.3 (2H, m), 7.2 (4H, m), 4.8 (2H, s),3.6 (2H,s)

Ex.239b (d⁷ -DMF) δ7.7 (1H, t), 7.4 (3H, m), 7.2 (3H,m), 7.1 (2H, m),4.7 (1H, d), 4.6 (1H, d), 3.5 (1H, dd), 3.0 (1H, dd), 2.9 (1H, dd), 2.7(1H, dd), 2.0 (3H, s), 1.7 (6H, m), 1.5 (6H, s)

Ex.239c (CDCl₃) δ9.0 (3H, d), 7.5 (10H, m), 5.5 (4H, s)

Ex.239d (CDCl₃) δ8.1 (1H, d), 7.5 (12H, m), 5.4 (4H, s), 3.8 (2H, bs)

Ex.239e (d⁶ -DMSO) δ10.5 (1H, s), 8.5 (2H, s), 8.2 (1H, s), 7.3 (15H,m), 5.4 (4H, s), 4.3 (1H, m), 2.9 (2H, m), 1.3 (9H,s

Ex.239g (d⁶ -DMSO) δ9.8 (1H, s), 8.4 (2H, s), 8.1 (1H, s), 8.0 (1H, d),7.1 (14H, m), 4.5 (2H, s), 4.2 (1H, s), 3.1 (2H, m), 2.8 (2H, m), 2.6(1H, m), 2.2 (1H, m), 1.7 (3H, s), 1.5 (6H, m), 1.1 (6H, s)

Ex.240 (d⁶ -DMSO) δ9.9 (1H, s), 8.3(2H, s), 8.1 (1H, s), 7.1 (15H, m),4.4 (3H, m), 3.1 (2H, m), 2.8 (2H, m),2.6 (1H, m), 2.2 (1H, m), 1.8 (3H,s), 1.5 (6H, m), 1.2 (6H, s)

Ex.241 (d⁶ -DMSO) δ9.8 (1H, s), 8.4 (2H, s), 8.1 (1H, s), 8.0 (1H, d),7.1 (14H, m), 4.5 (2H, s), 4.2 (1H, s), 3.1 (2H, m), 2.8 (2H, m), 2.6(1H, m), 2.2 (1H, m), 1.7 (3H, s), 1.5 (6H, m), 1.1 (6H, s)

Ex.242 (d⁶ -DMSO) δ9.9 (1H, s), 8.3 (2H, s), 8.1 (1H, s), 7.1 (15H, m),4.4 (3H, m), 3.1 (2H, m), 2.8 (2H, m), 2.6 (1H, m), 2.2 (1H, m), 1.8(3H, s), 1.5 (6H, m), 1.2 (6H, s)

Ex.243 (d⁶ -DMSO) δ10.1 and 9.8 (1H, 2×s), 8.4 (2H, d), 8.1 (1H, m), 7.7and 7.4 (1H, 2×m), 7.1 (9H, m), 4.5 (2H, m), 4.2 (1H, m), 3.2 (2H, m),2.9 (1H, m), 2.6 (1H, m), 2.2 (1H, m), 1.8-0.8 (28H, m)

Ex.244 (d⁶ -DMSO) δ9.8 (1H, s), 8.4 (2H, s), 8.1 (2H, s), 7.2 (12H, m),4.4 (3H, m), 3.0 (4H, m), 2.6 (1H, m), 2.2 (1H, m), 1.7 (3H, s), 1.5(6H, m), 1.1 (6H, s)

Ex.245 (d⁶ -DMSO) δ9.9 (1H, s), 8.3 (2H, s), 8.1 (1H, s), 7.1 (13H, m),4.5 (3H, m), 3.1 (2H, m), 2.8 (2H, m), 2.6 (1H, m), 2.2 (1H, m), 1.8(3H, s), 1.6 (6H, m), 1.2 (6H, m)

Ex.246 (d⁶ -DMSO) δ9.8 (1H, s), 8.4 (2H, s), 8.1 (1H, s), 8.0 (1H, d),7.2 (13H, m), 4.5 (2H, m), 4.2 (1H, s), 3.1 (2H, m), 2.8 (2H, m), 2.6(1H, m), 2.2 (1H, m), 1.7 (3H, s), 1.5 (6H, m), 1.1 (6H, s)

Ex.247 (d⁶ -DMSO) δ9.9 (1H, s), 8.3 (2H, s), 8.1 (1H, s), 7.1 (14H, m),4.5 (3H, m), 3.1 (1H, m), 2.8 (3H, m), 2.4 (2H, m), 1.8 (3H, s), 1.5(6H, m), 1.2 (6H, m)

Ex.248 (d⁶ -DMSO) δ9.8 (1H, s), 8.4 (2H, s), 8.1 (1H, s), 8.0 (1H, d),7.2 (13H, m), 4.5 (2H, m), 4.2 (1H, m), 3.1 (2H, m), 3.1 (2H, m), 2.6(1H, m), 2.2 (1H, m), 1.7 (3H, s), 1.5 (6H, m), 1.1 (6H, s)

Ex.249 (d⁶ -DMSO) δ9.9 (1H, s), 8.3 (2H, s), 8.1 (1H, s), 7.1 (14H, m),4.5 (3H, m), 3.1 (1H, m), 2.9 (3H, m), 2.4 (2H, m), 1.8 (3H, s), 1.5(6H, m), 1.2 (6H, m)

Ex.250 (d⁶ -DMSO) δ9.8 (1H, s), 8.4 (2H, s), 8.1 (1H, s), 7.9 (1H, d),7.2 (13H, m), 4.4 (2H, m), 4.2 (1H, m), 3.7 (3H, s), 3.0 (4H, m), 2.6(1H, m), 2.2 (1H, m), 1.7 (3H, s), 1.5 (6H, m), 1.1 (6H, s)

Ex.251 (d⁶ -DMSO) δ9.9 (1H, s), 8.3 (2H, s), 8.1 (1H, s), 7.1 (14H, m),4.4 (3H, m), 3.7 (3H, s), 3.1 (2H, m), 2.4 (2H, m), 1.8 (3H, s), 1.6(6H, m), 1.2 (6H, m)

Ex.252 (d⁶ -DMSO) δ13.2 (2H, br s), 9.9 (1H, s), 8.4 (2H, s), 8.1 (1H,s), 8.0 (1H, d), 7.9-6.8 (16H, m), 4.5 (2H, m), 4.0 (1H, s), 3.1 (2H,m), 2.8 (2H, m), 2.6 (1H, m), 2.2 (1H, m), 1.7 (3H, s), 1.5 (6H, m), 1.1(6H, s)

Ex.253 (d⁶ -DMSO) δ13.1 (2H, br s), 9.9 (1H, s), 8.3 (2H, s), 8.1 (1H,s), 7.9-6.8 (17H, m), 4.5 (3H, m), 3.1 (1H, m), 2.8 (3H, m), 2.4 (2H,m), 1.8 (3H, s), 1.5 (6H, m), 1.2 (6H, m)

Ex.254 (d⁶ -DMSO) δ13.2 (2H, br s), 9.8 (1H, s), 8.4 (2H, s), 8.1 (1H,s), 8.0 (1H, d), 7.2 (13H, m), 4.5 (2H, m), 4.2 (1H, s), 3.1 (2H, m),2.8 (2H, m), 2.6 (1H, m), 2.2 (1H, m), 1.7 (3H, s), 1.5 (6H, m), 1.1(6H, s)

Ex.255 (d⁶ -DMSO) δ13.2 (2H, br s), 9.9 (1H, s), 8.3 (2H, s), 8.1 (1H,s), 7.1 (14H, m), 4.5 (3H, m), 3.1 (1H, m), 2.8 (3H, m), 2.4 (2H, m),1.8 (3H, s), 1.5 (6H, m), 1.2 (6H, m)

Ex.256 (d⁶ -DMSO) δ13.2 (2H, br s), 9.8 (1H, s), 8.4 (2H, s), 8.1 (1H,s), 8.0 (1H, d), 7.2 (13H, m), 4.5 (2H, m), 4.2 (1H, s), 3.1 (2H, m),2.8 (2H, m), 2.6 (1H, m), 2.2 (1H, m), 1.7 (3H, s), 1.5 (6H, m), 1.1(6H, s)

Ex.257 (d⁶ -DMSO) δ13.2 (2H, br s), 9.9 (1H, s), 8.3 (2H, s), 8.1 (1H,s), 7.1 (14H, m), 4.5 (3H, m), 3.1 (1H, m), 2.8 (3H, m), 2.4 (2H, m),1.8 (3H, s), 1.5 (6H, m), 1.2 (6H, m)

Ex.258 (d⁶ -DMSO) δ13.2 (2H, br s), 11.1 and 9.8 (1H, 2×s), 8.2 (4H, m),7.2 (13H, m), 4.5-4.2 (3H, m), 3.2-2.4 (6H, mm), 17-1.1 (15H, m)

Ex.259 (d⁶ -DMSO) δ9.9 (1H, s), 8.3 (2H, s), 8.1 (1H, s), 7.1 (13H, m),4.5 (3H, m), 3.1 (2H, m), 2.8 (2H, m), 2.6 (1H, m), 2.2 (1H, m), 1.8(3H, s), 1.6 (6H, m), 1.2 (6H, m)

Ex.260 (CDCl₃) δ8.6 (1H, s), 7.6 (2H, d), 7.2 (16H, m), 5.8 (1H, m), 5.6(1H, m), 4.8 (1H, m), 4.5 (1H, d), 4.2 (1H, d), 3.2 (3H, m), 3.0 (1H,dd), 2.6 (1H, m), 2.4 (1H, m), 1.9 (3H, s), 1.6 (6H, m), 1.2 (6H, s)

Ex.261 (CDCl₃) δ8.8 (1H, s), 7.3 (18H, m), 6.1 (1H, m), 6.0 (1H, m), 5.0(1H, m), 4.4 (1H, d), 4.1 (1H, d), 3.7 (1H, dd), 3.2 (1H, m), 3.1-2.8(3H, m), 2.4 (1H, m), 2.0 (3H, s), 1.7 (6H, m), 1.3 (6H, s)

Ex.262 (d⁶ -DMSO) δ9.8 (1H, s), 9.2 (1H, br s), 8.4 (2H, s), 8.1 (1H,s), 8.0 (1H, d), 7.2 (11H, m), 6.6 (2H, d), 4.5 (1H, s), 4.4 (1H, m),4.2 (1H, s), 3.1 (2H, m), 2.8 (2H, m), 2.6 (1H, m), 2.2 (1H, m), 1.7(3H, s), 1.5 (6H, m), 1.1 (6H, s)

Ex.263 (d⁶ -DMSO) δ9.8 (1H, s), 9.2 (1H, s), 8.3 (2H, s), 8.1 (1H, s),7.1 (12H, m), 6.6 (2H, d), 4.4 (3H, m), 3.1 (1H, m), 2.8 (3H, m), 2.4(2H, m), 1.8 (3H, s), 1.5 (6H, m), 1.2 (6H, m)

Ex.264 (d⁶ -DMSO) δ9.8 (1H, s), 9.2 (1H, br s), 8.4 (2H, s), 8.1 (1H,s), 8.0 (1H, d), 7.2 (11H, m), 6.6 (2H, d), 4.5 (1H, s), 4.4 (1H, m),4.2 (1H, s), 3.1 (2H, m), 2.8 (2H, m), 2.6 (1H, m), 2.2 (1H, m), 1.7(3H, s), 1.5 (6H, m), 1.1 (6H, s)

Ex.265 (d⁶ -DMSO) δ9.8 (1H, s), 9.2 (1H, br s), 8.4 (2H, s), 8.1 (1H,s), 8.0 (1H, d), 7.2 (11H, m), 6.6 (2H, d), 4.5 (1H, s), 4.4 (1H, m),4.2 (1H, s), 3.1 (2H, m), 2.8 (2H, m), 2.6 (1H, m), 2.2 (1H, m), 1.7(3H, s), 1.5 (6H, m), 1.1 (6H, s)

Ex.266 (d⁶ -DMSO) δ9.8 (1H, s), 8.4 (2H, s), 8.1 (1H, d), 7.1 (14H, m),4.5 (2H, m), 4.2 (1H, s), 3.1 (3H, m), 2.7 (3H, m), 1.4-0.7 (13H, m)

Ex.267 (d⁶ -DMSO) δ9.9 (1H, s), 8.3 (2H, s), 8.1 (1H, s), 7.1 (15H, m),4.5 (3H, m), 3.1 (4H, m), 2.6 (2H, m), 1.4-0.7 (13H, m)

Ex.268 (d⁶ -DMSO) δ9.8 (1H, s), 8.4 (2H, s), 8.1 (1H, s), 8.0 (1H, d),7.1 (14H, m), 4.5 (2H, m), 4.2 (1H, s), 3.1 (3H, m), 2.7 (3H, m),1.4-0.7 (11H, m)

Ex.269 (d⁶ -DMSO) δ9.9 (1H, s), 8.3 (2H, s), 8.1 (1H, s), 7.1 (15H, m),4.5 (3H, m), 3.0 (4H, m), 2.6 (2H, m), 1.6-0.6 (11H, m)

Ex.270 (d⁶ -DMSO) δ13.1 (2H, br s), 9.8 (1H, s), 8.4 (2H, s), 8.3-6.8(23H, m), 4.7-4.2 (3H, m), 3.2 (4H, m), 2.7 (2H, m)

Ex.271 (d⁶ -DMSO) δ13.2 (2H, br s), 10.0 (1H, s), 8.3 (2H, s), 8.2-6.8(23H, m), 4.5 (3H, m), 3.2 (3H, m), 2.7 (3H, m)

Ex.272 (d⁶ -DMSO) δ9.6 (1H, s), 8.4-6.8 (21H, m), 4.7-4.1 (3H, m), 3.2(4H, m), 2.8 (2H, m)

Ex.273 (d⁶ -DMSO) δ9.8 (1H, s), 8.3-6.7 (21H, m), 4.5-4.1 (3H, m), 3.2(4H, m), 2.9 (2H, m)

Ex.274 (d⁶ -DMSO) δ13.1 (2H, br s), 10.1-9.7 (1H, (1H, 333 s), 8.4-7.0(18H, m), 4.5-4.1 (3H, m), 3.1 (2H, m), 2.8 (2H, m), 2.6 (2H, m), 2.0(2H, m), 1.7 (3H, s), 1.5 (6H, m), 1.1 (6H, )

Ex.275 (d⁶ -DMSO) δ13.1 (2H, br s), 10.1-9.7 (1H, 3×s), 8.4-7.0 (18H,m), 4.5-4.1 (3H, m), 3.1 (2H, m), 2.8 (2H, m), 2.6 (2H, m) 2.0 (2H, m),1.7 (3H, s), 1.5 (6H, m), 1.1 (6H, m)

Ex.276 (d⁶ -DMSO) δ13.2 (2H, br s), 11.0 and 10.9 (1H, 2×s), 9.9 and 9.7(1H, 2×s), 8.4-6.8 (15H, m), 6.5 and 6.3 (1H, 2×t), 4.5-4.1 (3H, m), 3.2(5H, m), 2.8 (2H, m), 2.6 (1H, m), 2.2 (1H, m), 1.7 (3H, m), 1.5 (6H,m), 1.1 (6H, m)

Ex.277 (d⁶ -DMSO) δ10.5 and 10.3 (1H, 2×s), 8.4-8.0 (3H, m), 7.2 (13H,m), 5.3 (1H, d), 4.5 (2H, m), 3.1 (2H, m), 2.5 (2H, m), 1.8 (3H, m), 1.5(6H, m), 1.2 (6H, m)

Ex.278 (d⁶ -DMSO) δ9.7 (1H, s), 8.2 (1H, s), 8.0 (1H, m), 7.8-6.9 (17H,m), 4.5 (1H, s), 4.4 (1H, s), 3.5-3.2 (2H, m), 2.9 (2H, m), 2.6 (1H, m),2.3 (1H, m), 1.7 (3H, s), 1.5 (6H, m), 1.4 (6H, s)

Ex.279 (d⁶ -DMSO) δ12.9 (1H, s), 9.7 (1H, s), 8.2 (1H, s), 7.6 (2H, t),7.4-7.2 (11H, m), 7.1 (2H, m), 7.0 (2H, q), 6.8 (1H, t), 4.5 (3H, m),3.2 (1H, dd), 3.0 (2H, m), 2.9 (1H, dd), 2.6 (1H, dd), 2.4 (1H, dd), 1.8(3H, s), 1.6 (6H, m), 1.3 (6H, s)

Ex.280 (d⁶ -DMSO) δ9.2-7.7 (5H, m), 7.3 (13H, m), 7.0 and 6.8 (1H, 2×t),5.0-4.2 (3H, m), 3.8 (3H, m), 3.4-2.5 (6H, m) 1.9 (3H, m), 1.5 (6H, m),1.1 (6H, m)

Ex.281 (d⁶ -DMSO) δ13.0 (2H, br s), 9.8 (1H, d), 8.0 (1H, d), 7.9-6.8(17H, m), 4.5-4.2 (3H, m), 3.1 (2H, m), 2.8 (2H, m), 2.6 (1H, m), 2.3(1H, m), 1.8 (3H, m), 1.5 (6H, m), 1.1 (6H, m)

Ex.282 (d⁶ -DMSO) δ9.8 (1H, m), 8.4-8.0 (3H, m), 7.1 (14H, m), 4.5 (3H,m), 3.0 (4H, m), 2.6 (1H, m), 2.2 (1H, m), 1.8 (3H, m), 1.5 (6H, m), 1.1(6H, s)

Ex.283 (d⁶ -DMSO) δ13.7 (1H, br s), 8.5 (2H, m), 8.2-7.9 (2H, m),7.6-6.4 (16H, m), 4.5 (1H, s), 4.4 (1H, m), 4.2 (1H, s), 3.5-3.2 (2H,m), 2.9 (2H, m), 2.6 (1H, m), 2.3 (1H, m), 1.7 (3H, m), 1.5 (6H, m), 1.0(6H, m)

Ex.284 (d⁶ -DMSO) δ12.9 (1H, br s), 9.7 (1H, s), 8.2 (1H, s), 7.6-7.0(17H, m), 6.8 (1H, t), 4.5 (3H, m), 3.2 (1H, m), 3.0 (2H, m), 2.9 (1H,m), 2.4 (1H, m), 1.8 (3H, m), 1.5 (6H, m), 1.3 (6H, m)

Ex.285 (d⁶ -DMSO) δ9.8 (1H, s), 8.0 (1H, s), 7.9 (1H, d), 7.8-6.9 (17H,m), 4.5 (2H, m), 4.2 (1H, m), 3.4-3.1 (2H, m), 2.8 (1H, d), 2.7-2.3 (3H,m), 1.9 (3H, m), 1.5 (6H, m), 1.2 (6H, m)

Ex.286 (d⁶ -DMSO) δ9.8 (1H, s), 8.4 (2H, s), 8.1 (1H, s), 8.0 (1H, d),7.1 (14H, m), 4.5 (2H, s), 4.2 (1H, s), 3.9 (6H, s), 3.1 (2H, m), 2.8(2H, m), 2.6 (1H, m), 2.2 (1H, m), 1.7 (3H, s), 1.5 (6H, m), 1.1 (6H, s)

Ex.287 (CDCl₃) δ9.2 and 9.1 (1H, 2×s), 8.4-8.0 (4H, m), 7.1 (14H, m),4.8 (1H, m), 4.5 (2H, m), 3.6-2.6 2.6 (4H, m), 1.7 (3H, m), 1.5 (6H, m),1.1 (6H, m), 0.7 (6H, m)

Ex.288 (d⁶ -DMSO) δ10.5 (1H, s), 9.9 (1H, s), 8.5 (2H, s), 8.1 (1H, s),7.9 (1H, d), 7.7 (1H, br t), 7.4-6.7 (18H, m), 4.6 (1H, m), 4.4 (1H, s),4.1 (1H, s), 3.3 (2H, m), 3.0 (2H, m), 2.9-2.7 (2H, m), 2.6 (2H, m)

Ex.289 (d⁶ -DMSO) δ13.2 (2H, br s), 10.8 (1H, s), 10.0 (1H, s), 8.3 (2H,d), 8.1 (1H, d), 7.6 (1H, br t), 7.5-6.8 (19H, m), 4.5 (1H, m), 4.45(1H, d), 4.37 (1H, d), 3.3-2.8 (6H, m), 2.7 (2H, m)

Ex.290 (d⁶ -DMSO) δ9.9 (1H, s), 8.5 (2H, s), 8.2 (1H, br s), 8.1 (1H,s), 7.4-6.7 (17H, m), 4.5 (2H, m), 4.2 (3H, m), 3.0 (4H, m)

Ex.291 (d⁶ -DMSO) δ13.2 (2H, br s), 10.0 (1H, br s), 8.5 (2H, s), 8.2(1H, br s), 8.1 (1H, s), 7.7 (1H, br s), 7.5-6.8 (18H, m), 4.5 (3H, m),3.0 (6H, m), 2.5 (2H, m)

Ex.292 (d⁶ -DMSO) δ13.2 (2H, br s), 10.0 (1H, 2×s), 8.3 (2H, s), 8.1(1H, br s), 8.0 (1H, d), 7.5-6.8 (19H, m), 4.5 (3H, m), 3.0 (6H, m), 2.0(2H, m), 1.5 (2H, t)

Ex.293 (d⁶ -DMSO) δ13.2 (1H, br s), 9.7 (1H, s), 8.2 (1H, s), 8.0 (1H,br s), 7.8 (1H, d), 7.6 (1H, d), 7.4-6.9 (13H, m), 4.5 (3H, m), 3.0 (4H,m), 2.4 (2H, m), 1.8 (3H, d), 1.5 (6H, m), 1.2 (6H, m)

Ex.294 (d⁶ -DMSO) δ13.0 (1H, br s), 9.7 (1H, s), 8.2 (1H, s), 7.6 (2H,m), 7.4-6.8 (14H, m), 4.5 (3H, m), 3.0 (4H, m), 2.4 (2H, m), 1.8 (3H,s), 1.5 (6H, q), 1.2 (6H, s)

Ex.295 (d⁶ -DMSO) δ13.0 (1H, br s), 9.7 (1H, s), 8.3 (1H, s), 8.2 (1H,br s), 8.0-6.9 (22H, m), 4.7-4.2 (5H, m), 3.0 (4H, m)

Ex.296 (d⁶ -DMSO) δ13.0 (1H, br s), 9.8 (1H, s), 8.2 (2H, br s), 8.0-6.9(22H, m), 4.7-4.2 (5H, m), 3.0 (4H, m)

Ex.297 (d⁶ -DMSO) δ12.8 (1H, br s), 9.8 (1H, s), 8.3 (1H, br s), 8.2(1H, s), 8.0-6.9 (24H, m), 4.7-4.2 (5H, m), 3.0 (4H, m)

Ex.298 (d⁶ -DMSO) δ12.8 (1H, br s), 9.8 (1H, s), 8.4 (1H, br s), 8.3(1H, s), 8.0-6.9 (24H, m), 4.7-4.2 (5H, m), 3.0 (4H, m)

Ex.299 (d⁶ -DMSO) δ8.3 (2H, m), 8.0 (2H, s), 7.8 (1H, d), 7.4 (1H, t),7.3-6.9 (13H, m), 4.5 (1H, s), 4.3 (3H, m), 4.1 (1H, s), 3.2-2.4 (6H,m), 1.8 (3H, m), 1.5 (6H, m), 1.2 (6H, m)

Ex.300 (d⁶ -DMSO) δ8.3 (2H, m), 8.0 (2H, s), 7.4-7.0 (12H, t), 6.9 (3H,m), 4.4 (2H, 2×s), 4.3 (1H, m), 4.2 (2H, m), 3.2-2.4 (6H, m), 1.8 (3H,m), 1.6 (6H, m), 1.2 (6H, m)

Ex.301 (d⁶ -DMSO) δ13.2 (2H, br s), 9.8 (1H, s), 8.4 (2H, s), 8.3 (1H,m), 8.1 (2H, m), 7.7 (3H, m), 7.5 (1H, s), 7.3 (9H, m), 7.2 (2H, m), 7.1(2H, m), 6.9 (3H, s), 4.6 (1H, s), 4.55 (1H, m), 4.4 (1H, m), 4.3 (1H,s), 4.1 (1H, m), 3.2 (2H, m), 2.9 (1H, m), 2.8 (1H, m)

Ex.302 (d⁶ -DMSO) δ13.2 (2H, br s), 9.9 (1H, s), 8.4 (2H, s), 8.3 (1H,m), 8.1 (2H, m), 7.7 (3H, m), 7.5 (1H, s), 7.3 (9H, m), 7.2 (2H, m), 7.1(2H, m), 6.9 (3H, s), 4.6 (1H, s), 4.55 (1H, m), 4.4 (1H, m), 4.3 (1H,s), 4.1 (1H, m), 3.2 (2H, m), 2.9 (1H, m), 2.8 (1H, m)

The compounds of the examples were tested for binding at the CCK_(B)receptor in mouse cortical membranes by means of a radioligand bindingassay. The procedure was as follows:

The whole brains from male mice (CD1 22-25 g; Charles River) wereremoved and placed in ice-cold buffer (pH 7.2@21°±3° C.) of thefollowing composition (mM); 10 HEPES, 130 NaCl, 4.7 KCl, 5 MgCl₂, 1 EDTAand containing 0.25 g.l⁻¹ bacitracin. The cortex was dissected, weighedand homogenised in 40 ml ice-cold buffer using a Teflon-in-glasshomogeniser. The homogenate was centrifuged at 39,800 g for 20 min at 4°C., the supernatant discarded and the pellet resuspended byhomogenisation in fresh buffer. The homogenate was recentrifuged (39,800g; 20 min @4° C.) and the final pellet was resuspended in HEPES bufferto give a tissue concentration of 2 mg.ml⁻¹ (original wet weight).

The membranes (400 ml) were incubated for 150 min at 21°±3° C. in afinal volume of 0.5 ml with HEPES buffer containing ¹²⁵ I!-CCK8S (0.05ml; 200 pM NEN 2200 Ci.mmol⁻¹) and competing compound. Total andnon-specific binding of ¹²⁵ I!-CCK8S were defined using 0.05 ml ofbuffer and 0.05 ml of 10 mM L-365,260, respectively. The assay wasterminated by rapid filtration through pre-soaked Whatman GF/B filtersusing a Brandell Cell harvester. The filters were washed (3×3 ml) withice-cold 50 mM Tris-HCl (pH 7.4 @4° C.) and bound radioactivitydetermined by counting (1 min.) in a gamma-counter.

The results obtained from the CCK_(B) assays are set out in Table 1.

                  TABLE 1    ______________________________________    Example  CCK.sub.B pK.sub.i                           Example  CCK.sub.B pK.sub.i    ______________________________________    1        5.0           32       5.5    2        5.1           33       6.0    3        4.8           34       6.6    4        5.6           35       5.1    5        5.3           36       6.1    6        5.3           37       6.6    7        4.8           38       6.0    8        5.2           39       5.8    9        5.0           40       6.0    10       4.8           42       6.8    11       5.0           43       6.2    12       6.2           44       5.3    13       6.0           45       5.2    14       6.3           46       6.1    15       5.8           47       6.3    16       5.7           48       6.0    17       5.7           49       5.9    19       4.5           50       6.6    20       5.5           51       7.2    21       5.2           52       6.6    23       5.5           53       6.5    24       5.9           54       6.1    25       6.7           55       6.1    26       5.5           56       6.6    27       6.9           57       6.7    28       5.9           58       6.6    29       5.9           59       5.6    30       5.7           60       6.4    31       5.5           61       5.9    62       5.6           94       5.2    63       5.9           95       5.5    64       5.3           96       6.7    65       6.5           97       5.9    66       6.2           98       6.7    67       5.6           99       5.5    68       5.9           100      6.2    69       6.2           101      5.6    70       5.0           102      5.6    71       5.8           103      5.2    72       5.8           104      4.9    73       5.3           105      6.2    74       7.3           106      4.5    75       5.9           107      4.2    76       5.7           108      4.7    77       6.5           110      4.9    78       6.2           111      7.0    79       5.5           112      5.7    80       5.8           113      5.6    81       7.3           114      5.3    82       5.1           115      6.0    83       5.1           116      5.7    84       5.2           117      5.3    85       5.8           118      6.1    86       6.2           119      6.7    87       5.3           120      7.0    88       5.3           121      4.8    89       6.1           122      6.2    92       5.6           123      5.8    93       5.3           124      5.8    125      5.5           156      7.3    126      5.4           157      6.7    127      5.3           158      5.7    128      5.8           159      4.6    129      6.5           160      6.4    130      6.3           161      6.2    131      7.4           162      5.6    132      6.5           163      5.0    133      6.1           164      6.3    134      5.9           165      6.0    135      6.3           166      6.0    136      6.3           167      5.0    137      5.8           168      5.1    138      4.6           169      5.1    139      5.3           170      5.4    140      5.0           171      6.7    141      5.8           172      5.8    142      5.9           173      6.1    143      7.2           174      6.1    144      6.2           175      6.1    145      6.2           176      5.2    147      6.3           177      5.5    148      5.2           178      5.3    149      6.1           179      5.2    150      5.4           180      6.3    151      6.6           181      5.5    152      6.0           182      5.5    153      6.2           183      6.3    154      6.5           184      6.2    155      6.5           185      6.8    186      7.1           216      6.3    187      6.2           217      6.3    188      6.2           218      6.4    189      5.7           219      6.2    190      5.8           220      7.0    191      5.2           227      5.0    192      5.3           228      5.4    193      5.5           229      5.5    194      5.8           230      5.3    195      6.1           233      6.5    196      6.2           234      6.5    197      4.5           236      6.7    198      5.1           237      6.7    199      6.1           238      7.6    200      5.0           239      8.8    201      6.5           240      7.8    202      5.2           241      8.0    203      5.9           242      7.8    204      6.0           243      7.6    205      6.7           244      8.6    206      6.9           245      7.3    207      5.5           246      7.9    208      6.2           247      7.3    209      6.5           248      8.0    210      5.2           249      6.6    211      5.8           250      7.0    212      6.1           251      6.3    213      5.8           252      6.5    214      5.7           253      6.7    215      6.1           254      8.5    255      8.2           280      7.5    256      8.5           281      7.0    257      8.0           282      6.5    258      8.0           283      6.7    259      7.3           284      6.8    260      5.4           285      6.9    261      5.4           286      5.0    262      8.8           287      7.2    265      7.8           288      7.8    266      8.4           289      7.1    267      7.4           290      7.3    268      7.7           291      8.4    269      6.7           292      7.5    270      8.0           293      8.2    271      6.5           294      7.6    272      7.4           295      7.2    273      6.8           296      6.3    274      7.2           297      7.2    275      7.0           298      6.4    276      7.3           299      7.5    277      6.3           300      7.4    278      7.8           301      8.6    279      6.8           302      8.3    ______________________________________

The compounds of the examples were also tested for gastrin antagonistactivity in an immature rat stomach assay. The procedure was as follows:The oesophagus of immature rats (33-50 g, ca. 21 days old) was ligatedat the level of the cardiac sphincter and the duodenal sphincter wascannulated. The stomach was excised and flushed with ca. 1 ml ofunbuffered physiological saline solution. The fundus was punctured andcannulated. A further 4-5 ml of unbuffered solution was flushed throughthe stomach to ensure the preparation was not leaking. The stomach waslowered into a jacketed organ bath containing 40 ml of buffered solutioncontaining 3×10⁻⁸ M 5-methylfurmethide, maintained at 37° and gassedvigorously with 95% O₂ /5% Co₂. The stomach was continuously perfused ata rate of 1 ml min⁻¹ with unbuffered solution gassed with 100% O₂ withthe perfusate passing over an internally referenced pH-electrode fixed12 cm above the stomach.

After 120 min of stabilisation the drugs were added directly to theserosal solution in the organ bath and after a further 60 min cumulativepentagastrin dose-response curves were started. Changes in acidsecretion were monitored and the curves analysed according to Blacket.al., Br. J. Pharmacol., 1985, 86, 581.

The results obtained from the gastrin assays are set out in Table 2.

                  TABLE 2    ______________________________________    Example  Gastrin pK.sub.B                           Example  Gastrin pK.sub.B    ______________________________________    12       4.8           78       6.9    13       5.8           79       5.6    14       5.9           81       5.9    15       5.7           83       5.4    16       5.6           84       5.6    22       5.2           85       6.2    23       5.2           90       4.6    24       5.7           91       4.6    25       6.7           94       4.9    27       6.5           99       5.6    28       6.0           103      5.9    29       5.8           109      5.6    35       5.7           112      6.2    36       5.5           113      4.9    39       4.7           119      6.9    41       5.5           120      6.9    48       6.6           122      6.7    49       5.8           123      7.2    50       6.1           124      6.5    51       5.6           129      6.7    56       5.2           131      6.0    62       5.3           132      5.7    64       5.2           133      6.9    65       5.4           136      6.0    67       5.1           142      6.1    68       6.5           143      6.9    69       7.1           144      5.6    70       5.7           145      6.3    71       5.7           147      6.9    73       5.8           149      6.2    151      5.9           206      6.0    156      5.7           209      5.7    158      6.4           210      5.1    160      7.0           211      6.0    161      6.6           213      6.1    162      6.1           214      6.6    164      6.6           215      5.5    165      5.9           220      7.3    166      5.7           227      6.2    167      5.5           228      5.8    171      6.5           229      6.4    172      5.4           230      5.8    173      5.8           233      6.4    180      6.2           234      5.5    181      5.7           236      6.9    183      6.5           237      6.8    184      6.6           239      8.8    185      7.1           240      7.8    186      7.3           241      8.0    187      6.9           242      7.8    188      7.3           243      7.6    189      6.9           244      8.6    195      6.9           245      7.3    196      7.0           246      7.9    198      5.2           247      7.3    199      6.3           248      8.0    201      7.0           249      6.6    203      6.4           250      7.0    204      6.1           251      6.3    205      6.2           252      6.5    253      5.8           273      6.0    254      8.6           274      7.5    255      8.0           275      7.2    256      8.4           276      7.1    257      7.6           277      6.4    258      8.2           278      5.7    259      7.2           279      5.7    261      6.6           280      5.8    262      8.9           281      6.1    263      7.2           282      6.9    264      6.8           284      5.7    265      8.1           287      8.0    266      8.4           291      7.1    267      7.0           299      7.4    268      7.3           300      7.2    269      6.6           301      7.4    270      7.6           302      6.5    272      6.5    ______________________________________

The compounds of the examples were also tested in a CCK_(A) bindingassay as follows:

The pancreatata were removed from male guinea-pigs (200-300 g; DunkinHartley) and placed in ice-cold HEPES buffer (pH 7.2 @21±3°). Thepancreatata were homogenised in 40 ml ice-cold HEPES buffer using apolytron (Brinkmann, PT10, setting 10) 4×1 second. The homogenate wascentrifuged at 39,800 g for 15 min at 4°. The supernatant was discardedand the pellet re-suspended using a Teflon-in-glass homogeniser in 20volumes of fresh buffer and re-centrifuged as above. The final pelletwas re-suspended using a Teflon-in-glass homogeniser to a tissueconcentration of 1 mg.ml⁻¹ (original wet weight), and filtered through500 μm pore-size Nytex mesh.

The membranes (400 μl; containing 0.375 μM PD134,308) are incubated for150 minutes at 21±3° in a final volume of 0.5 ml with HEPES buffercontaining ¹²⁵ I!-CCK₈ (S) (50 μl; 200 pM) and competing compound. Totaland non-specific binding of ¹²⁵ I!-CCK₈ (S) are defined using 50 μl ofbuffer and 50 μl of 100 nM L-364,718 respectively. The assay isterminated by rapid filtration through pre-soaked Whatman GF/B filtersusing a Brandell Cell Harvester. The filters were washed (3×3 ml) withice-cold 50 mM Tris HCl (pH 7.4 at 4°) and bound radioactivity isdetermined by counting (1 min) in a gamma counter.

The results are set out in Table 3.

                  TABLE 3    ______________________________________    Example  CCK.sub.A pK.sub.i                           Example  CCK.sub.A pK.sub.i    ______________________________________    3        5.3           52       6.0    6        4.8           53       5.3    7        5.4           54       5.9    8        5.3           55       6.6    9        5.1           57       6.7    11       4.9           58       6.4    12       5.7           60       5.2    13       5.5           61       5.3    14       5.1           62       4.8    15       4.7           63       5.1    22       5.3           64       5.1    24       5.2           65       5.9    27       5.4           66       5.4    28       5.0           67       5.0    30       4.6           69       5.1    32       4.7           70       4.8    33       4.9           71       4.9    34       5.5           73       5.4    35       4.9           74       4.9    36       5.5           75       5.4    37       5.1           76       5.3    38       5.2           77       5.2    39       4.9           78       5.1    40       5.1           79       5.1    41       4.8           80       4.8    42       4.8           81       5.3    44       5.1           82       5.3    45       5.3           83       4.9    48       5.1           84       4.9    49       4.9           85       5.0    51       5.5           86       5.6    87       5.0           122      5.1    88       4.9           123      5.6    89       5.3           124      5.3    90       4.8           125      4.9    91       4.7           126      5.3    92       5.8           127      4.8    93       5.8           128      5.1    94       5.2           129      4.9    95       5.1           130      5.0    96       5.5           131      5.0    97       5.1           132      5.0    98       5.2           133      5.2    99       5.0           134      5.4    100      5.3           135      5.1    101      4.9           137      5.2    102      5.3           138      5.2    103      5.2           139      5.2    104      5.2           140      5.2    105      5.3           141      4.8    107      4.5           142      5.4    108      5.5           143      5.3    111      5.6           144      5.6    112      5.9           145      5.2    113      5.4           146      4.9    114      5.5           147      5.3    115      5.3           148      5.7    117      5.7           149      5.2    118      5.6           150      5.1    119      4.8           151      5.5    120      5.4           152      5.5    121      5.0           153      5.5    154      5.5           186      4.6    155      5.2           187      5.2    156      5.3           189      5.9    157      5.7           190      4.9    158      5.1           191      5.1    159      5.7           192      5.0    160      5.1           193      5.2    162      5.6           194      5.1    163      5.9           195      5.9    164      4.4           196      5.9    165      5.3           197      5.7    166      5.2           199      5.9    167      5.0           200      5.5    168      4.8           201      5.1    169      5.7           202      4.9    170      5.2           203      5.2    171      5.8           205      5.3    172      5.6           206      5.7    173      5.4           207      6.6    174      6.2           208      5.7    175      5.3           209      5.3    176      4.7           210      5.1    177      5.8           212      5.1    178      4.9           213      5.1    179      5.0           214      5.5    180      4.4           215      4.5    181      4.9           219      5.6    182      5.3           220      6.3    183      5.1           227      6.3    184      5.1           228      5.4    185      4.9           229      5.5    239      5.7           271      5.9    240      6.3           272      6.6    241      5.6           273      5.9    242      5.9           274      5.7    243      6.0           275      5.7    244      5.7           276      6.5    245      6.3           277      5.6    246      6.0           278      6.0    247      6.4           279      6.0    248      6.1           280      5.7    249      7.3           281      5.9    250      5.8           283      5.9    251      5.7           287      5.6    252      6.1           288      6.4    253      7.0           289      5.8    254      6.0           290      6.8    255      6.1           291      5.5    256      6.5           292      5.8    257      6.4           293      6.1    258      5.7           294      6.0    259      5.9           299      5.6    260      5.9           300      5.6    268      5.4           301      5.8    269      5.9           302      5.8    270      6.3    ______________________________________

We claim:
 1. A compound of the formula ##STR20## wherein W is acarbonyl, sulphonyl or sulphinyl group, or, W is H when Z is absent andX is a carbonyl, sulphonyl or sulphinyl group or --C(O)--CH₂ -- (inwhich the carbonyl group is bonded to Y), provided that at least one ofW and X contains carbonyl,Y is R₇ --O-- or R₇ --N(R₈)-- (wherein R₇ is Hor C₁ to C₁₅ hydrocarbyl, up to two carbon atoms of the hydrocarbylmoiety optionally being replaced by a nitrogen, oxygen or sulphur atomprovided that Y does not contain a --O--O-- group, and R₈ is H, C₁ to C₃alkyl, carboxymethyl or esterified carboxymethyl), Z is selected fromi)--O--R₉ wherein R₉ is H, C₁ to C₅ alkyl, phenyl, substituted phenyl,benzyl or substituted benzyl; ii) ##STR21## wherein Q is H, C₁ to C₅hydrocarbyl, or --R₁₀ --U, wherein R₁₀ is a bond or C₁ to C₃ alkyleneand U is aryl, substituted aryl, heterocyclic, substituted heterocyclicor cycloalkyl; ##STR22## iii) wherein a is 0 or 1 and b is from 0 to3,R₁₁ is H or methyl, R₁₂ is H or C₁ to C₃ alkyl; or R₁₂ is CH₂ ═ and Q'is absent; or R₁₁ and R₁₂ are linked to form a 3- to 7-membered ring,R₁₃ is a bond or C₁ to C₅ hydrocarbylene, G is a bond, --CHOH-- or--C(O)-- Q' is as recited above for Q or --R₁₀ --(C(O))_(d)--L--(C(O))_(e) --R₉ (wherein R₉ and R₁₀ are as defined above, L is O, Sor --N(R₁₄)--, in which R₁₄ is as defined above for R₈, and d and e are0 or 1, provided that d+e<2); or Q'and R₁₂, together with the carbonatom to which they are attached, form a 3- to 7-membered ring, Q is asdefined above; or Q and R₁₂ together form a group of the formula--(CH₂)_(f) --V--(CH₂)_(g) -- wherein V is --S--, --S(O)--, --S(O)₂ --,--CH₂ --, or --C(O)--, f is from 0 to 2 and g is from 0 to 3; or, whenQ' is --R₁₀ --U and U is an aromatic group, Q may additionally representa methylene link to U, which link is ortho to the R₁₀ link to U, T is H,cyano, C₁ to C₄ alkyl, --CH₂ OH, carboxy, esterified carboxy or amidatedcarboxy; or iv) ##STR23## wherein A and B are independently a bond or C₁to C₃ alkylene, provided that A and B together provide from 2 to 4carbon atoms in the ring, R₉ and R₁₀ are as defined above, and R₁₅ is asdefined above for R₈ or Z is absent and W is H, R₁ is H, methyl, halo,carboxy, esterified carboxy, amidated carboxy, carboxymethyl, esterifiedcarboxymethyl or amidated carboxymethyl, R₂ is selected from the groupsrecited above for R₁ ; or, when Z is absent and W is H, R₂ mayadditionally represent --C(O)--Z' wherein Z' is selected from the groupsrecited above for Z; or R₁ and R₂ together form a second bond betweenthe carbon atoms to which they are attached, R₃ and R₄ (or each R₃ andR₄ group, when m or n is 2 or more) are independently selected fromhalo, amino, nitro, cyano, sulphamoyl, sulphonyl, trifluoromethyl, C₁ toC₃ alkyl, C₁ to C₃ alkoxy, hydroxy, C₁ to C₃ hydroxyalkyl, C₁ to C₃alkylcarboxyamino, carboxy, esterified carboxy and amidated carboxy, R₅and R₆ are independently selected from H and the groups recited abovefor R₃ m is from 0 to 4, provided that m is not more than 2 unless R₁ isexclusively halo, n is from 0 to 4, provided that n is not more than 2unless R₄ is exclusively halo,or a pharmaceutically acceptable saltthereof, provided that if one (but only one) of R₁ and R₂ is methyl, mand n are not both 0, Z is not hydroxy or methoxy when Y is hydroxy ormethoxy, Z and Y are not trans to each other when Z is R₈ --O-- and Y isR₇ --O--, --X--Y is not equal to --W--Z when R₁ ═R₂ ═H and m═n═0, and ifZ is absent and R₁ and R₂ are both H or form part of a double bond, Y isnot R₇ --O--,and further provided that said compound is not7-(N,N-dimethylaminocarbonyl)-8-methyl-2,3,5,6-dibenzobicyclo2.2.2!octane or7-(N-methyl-N-phenylaminocarbonyl)-8-methyl-2,3,5,6-dibenzobicyclo2.2.2!octane.
 2. A compound according to claim 1 wherein R₇ is C₆ to C₈straight or branched chain alkyl, or R₂₅ -(CH₂)_(p) -, wherein R₂₅ isselected from phenyl, 1-naphthyl, 2-naphthyl, indoyl, norbornyl,adamantyl or cyclohexyl, and p is from 0 to
 3. 3. A compound accordingto claim 1 wherein W is carbonyl and X is sulphonyl.
 4. A compoundaccording to claim 1 wherein W is carbonyl and X is carbonyl.
 5. Acompound according to claim 1 wherein W is sulphonyl and X is carbonyl.6. A compound according to claim 1 wherein R₁ and R₂ are both H.
 7. Acompound according to claim 1 wherein m and n are both
 0. 8. A compoundaccording to claim 1 of the formula ##STR24## wherein R₁, R₂, R₃, R₄,R₅, R₆, R₇, R₈, R₁₂ and U are as defined in claim 1,R₂₆ is H or C₁ to C₃alkyl, and R₂₇ is ##STR25## (wherein R₂₈ is H or C₁ to C₃ alkyl, R₂₉ is--CO₂ H or tetrazolyl, R₃₀ is H, --CO₂ H, tetrazolyl, --CH₂ OH, --CO₂ Meor --CONH₂, and y is from 0 to 2),or a pharmaceutically acceptable saltthereof.
 9. A pharmaceutical composition comprising a compound accordingto claim 8, together with a pharmaceutically acceptable diluent orcarrier.
 10. A pharmaceutical composition comprising a compoundaccording to claim 1, together with a pharmaceutically acceptablediluent or carrier.
 11. A compound according to claim 1 of the formula##STR26## wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₁₂ and U are asdefined in claim 1, R₂₆ is H or C₁ to C₃ alkyl andR₂₇ is ##STR27##wherein R₂₈ is H or C₁ to C₃ alkyl, R₂₉ is esterified carboxy oramidated carboxy and R₃₀ is H, --CO₂ H, esterified carboxy, amidatedcarboxy, tetrazolyl or --CH₂ OH, or R₂₉ is --CO₂ H or tetrazolyl and R₃₀is esterified carboxy or amidated carboxy, and y is 0, 1 or 2,or apharmaceutically acceptable salt thereof.
 12. A method for counteractingan effect of cholecystokinin or gastrin in a patient, said methodcomprising administering to said patient an effective amount of acompound of the formula ##STR28## wherein W is a carbonyl, sulphonyl orsulphinyl group, or, W is H when Z is absent and X is a carbonyl,sulphonyl or sulphinyl group or --C(O)--CH₂ --(in which the carbonylgroup is bonded to Y), provided that at least one of W and X containscarbonyl,Y is R₇ --O-- or R₇ --N(R₈)-- (wherein R₇ is H or C₁ to C₁₅hydrocarbyl, up to two carbon atoms of the hydrocarbyl moiety optionallybeing replaced by a nitrogen, oxygen or sulphur atom provided that Ydoes not contain a --O--O-- group, and R₈ is H, C₁ to C₃ alkyl,carboxymethyl or esterified carboxymethyl), Z is selected fromi) --O--R₉wherein R₉ is H, C₁ to C₅ alkyl, phenyl, substituted phenyl, benzyl orsubstituted benzyl;ii) ##STR29## wherein Q is H, C₁ to C₅ hydrocarbyl,or --R₁₀ --U, wherein R₁₀ is a bond or C₁ to C₃ alkylene and U is aryl,substituted aryl, heterocyclic, substituted heterocyclic or cycloalkyl;iii) ##STR30## wherein a is 0 or 1 and b is from 0 to 3, R₁₁ is H ormethyl,R₁₂ is H or C₁ to C₃ alkyl; or R₁₂ is CH₂ ═ and Q' is absent; orR₁₁ and R₁₂ are linked to form a 3- to 7- membered ring, R₁₃ is a bondor C₁ to C₅ hydrocarbylene, G is a bond, --CHOH-- or --C(O)-- Q' is asrecited above for Q or --R₁₀ --(C(O))_(d) --L--(C(O))_(e) --R₉ (whereinR₉ and R₁₀ are as defined above, L is O, S or --N(R₁₄)--, in which R₁₄is as defined above for R₈, and d and e are 0 or 1, provided thatd+e<2); or Q' and R₁₂, together with the carbon atom to which they areattached, form a 3- to 7-membered ring, Q is as defined above; or Q andR₁₂ together form a group of the formula --(CH₂)_(f) --V--(CH₂)_(g)--wherein V is --S--, --S(O)--, --S(O)₂ --, --CH₂ --, --CHOH-- or--C(O)--, f is from 0 to 2 and g is from 0 to 3; or, when Q' is --R₁₀--U and U is an aromatic group, Q may additionally represent a methylenelink to U, which link is ortho to the R₁₀ link to U, T is H, cyano, C₁to C₄ alkyl, --CH₂ OH, carboxy, esterified carboxy or amidated carboxy;or iv) ##STR31## wherein A and B are independently a bond or C₁ to C₃alkylene, provided that A and B together provide from 2 to 4 carbonatoms in the ring, R₉ and R₁₀ are as defined above, and R₁₅ is asdefined above for R₈ or Z is absent and W is H, R₁ is H, methyl, halo,carboxy, esterified carboxy, amidated carboxy, carboxymethyl, esterifiedcarboxymethyl or amidated carboxymethyl, R₂ is selected from the groupsrecited above for R₁ ; or, when Z is absent and W is H, R₂ mayadditionally represent --C(O)--Z' wherein Z' is selected from the groupsrecited above for Z; or R₁ and R₂ together form a second bond betweenthe carbon atoms to which they are attached, R₃ and R₄ (or each R₃ andR₄ group, when m or n is 2 or more) are independently selected fromhalo, amino, nitro, cyano, sulphamoyl, sulphonyl, trifluoromethyl, C₁ toC₃ alkyl, C₁ to C₃ alkoxy, hydroxy, C₁ to C₃ hydroxyalkyl, C₁ to C₃alkylcarboxyamino, carboxy, esterified carboxy and amidated carboxy R₅and R₆ are independently selected from H and the groups recited abovefor R₃ m is from 0 to 4, provided that m is not more than 2 unless R₃ isexclusively halo, n is from 0 to 4, provided that n is not more than 2unless R₄ is exclusively halo,or a pharmaceutically acceptable saltthereof.
 13. A method according to claim 12 wherein R₇ is C₆ to C₈straight or branched chain alkyl or cycloalkyl, or R₂₅ --(CH₂)_(p) --,wherein R₂₅ is selected from phenyl, 1-naphthyl, 2-naphthyl, indolyl,norbornyl, 1-adamantyl, 2-adamantyl, cyclohexyl or cycloheptyl, and p isfrom 0 to
 3. 14. A method according to claim 12 wherein W is carbonyland X is sulphonyl.
 15. A method according to claim 12 wherein W iscarbonyl and X is carbonyl.
 16. A method according to claim 12 wherein Wis sulphonyl and X is carbonyl.
 17. A method according to claim 12wherein R₁ and R₂ are both H.
 18. A method according to claim 12 whereinm and n are both
 0. 19. A method according to claim 12 comprisingadministering to said patient an effective amount of a compound of theformula ##STR32## wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₁₂ and U areas defined in claim 12,R₂₆ is H or C₁ to C₃ alkyl, and R₂₇ is ##STR33##(wherein R₂₈ is H or C₁ to C₃ alkyl, R₂₉ is --CO₂ H or tetrazolyl, R₃₀is H, --CO₂ H, tetrazolyl, --CH₂ OH, --CO₂ Me or --CONH₂, and y is from0 to 2).